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Pharmacology & Therapeutics
Volume 86, Issue 2 SummaryPlus
May 2000 Article
Pages 111-144 Journal Format-PDF (370 K)

PII: S0163-7258(00)00036-X
Copyright (c) 2000 Elsevier Science Inc. All rights reserved.

Review article

Factors influencing the processing and function of the amyloid precursor protein°°a potential therapeutic target in Alzheimer's disease?

Christine M. Coughlana and Kieran C. Breen, , b

a Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical School, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
b Dundee Alzheimer's Disease Research Centre, Department of Pharmacology and Neuroscience, University of Dundee, Ninewells Hospital Medical School, Dundee DD1 9SY, UK

Available online 2 May 2000.


The amyloid precursor protein (APP), which plays a pivotal role in Alzheimer's disease (AD), can exist as either a membrane-bound or soluble protein. The former is cleaved at the level of the plasma membrane to generate the soluble form of the protein (APPs). An alternative pathway exists, however, for the cleavage of APP to generate a 40°42 amino acid peptide termed amyloid (A), either within the lysosomal or the endoplasmic reticulum/Golgi compartments of the cell. In AD, there is an increase in the ratio of the 42 amino acid form of the A peptide (A42) to A40. The A42 form is the more amyloidogenic form and has an increased potential to form the insoluble amyloid deposits characteristic of AD pathology. Studies on the familial form of the disease, with mutations in APP or in the presenilin proteins, have confirmed an increase in A42 generation associated with the early stages of the disease. This review will examine the factors that influence APP processing, how they may act to modulate the biological effects of APPs and A, and if they provide a viable target for therapeutic intervention to modify the rate of progression of the disease.

Author Keywords: Alzheimer's disease; Amyloid; Presenilins; Apolipoprotein E; Inflammation; Calcium

Abbreviations: 2M, 2-macroglobulin protein; APP, amyloid precursor protein; AD, Alzheimer's disease; APLP, amyloid precursor-like protein; ApoE, apolipoprotein E; CAM, cell adhesion molecule; cAMP, cyclic AMP; CCV, clathrin-coated vesicle; cGMP, cyclic GMP; CTF, C-terminal fragment; DAG, diacylglycerol; DS, Down's syndrome; EGF, epidermal growth factor; E/L, endosomal/lysosomal; ER, endoplasmic reticulum; ERAB, endoplasmic reticulum amyloid peptide-binding protein; ERK, extracellular signal-regulated kinase; FAD, familial Alzheimer's disease; HSPG, heparan sulfate proteoglycan; IL, interleukin; KPI, Kunitz protease inhibitor; LDL, low-density lipoprotein; LRP, low-density lipoprotein receptor-related protein; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; mAChR, muscarinic acetylcholine receptor; NFB, nuclear factor B; NGF, nerve growth factor; PI, phosphatidylinositol; PKA, protein kinase A; PKC, protein kinase C; PL, phospholipase; PS, presenilin; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; TGF, transforming growth factor; TGN, trans-Golgi network; UV-DDP, UV-damaged DNA-binding protein

Article Outline

1. Introduction
2. Amyloid precursor protein function
2.1. Cell adhesion
2.2. Neurotrophic actions of amyloid precursor protein
2.3. Amyloid precursor protein interaction with membrane-bound proteins
3. Amyloid precursor protein processing
3.1. Intracellular transport of amyloid precursor protein
3.2. Caveolae and cholesterol
3.3. The role of membrane-bound proteins in amyloid precursor protein processing
3.4. Presenilins
3.5. Protein kinase C
3.6. Muscarinic receptors
3.7. Growth factors
3.8. Thrombin
3.9. The inflammatory response
3.10. Other agents
4. Amyloid function
4.1. Amyloid aggregation
4.2. Calcium and amyloid toxicity
4.3. Amyloid and the cytoskeleton
4.4. Neurotransmitter modulation of amyloid toxicity
4.5. Presenilins
4.6. Apolipoprotein E
4.7. 2-Macroglobulin
4.8. The inflammatory response
4.9. The C100 protein
5. Conclusion


Introduction 112

Amyloid precursor protein function 112

Cell adhesion 113

Neurotrophic actions of amyloid precursor protein 115

Amyloid precursor protein interaction with membrane-bound proteins 116

Amyloid precursor protein processing 117

Intracellular transport of amyloid precursor protein 118

Caveolae and cholesterol 118

The role of membrane-bound proteins in amyloid precursor protein processing 120

Presenilins 121

Protein kinase C 121

Muscarinic receptors 122

Growth factors 123

Thrombin 123

The inflammatory response 124

Other agents 124

Amyloid function 125

Amyloid aggregation 125

Calcium and amyloid toxicity 125

Amyloid and the cytoskeleton 127

Neurotransmitter modulation of amyloid toxicity 127

Presenilins 127

Apolipoprotein E 128

2-Macroglobulin 128

The inflammatory response 128

The C100 protein 129

Conclusion 130

Acknowledgments 130

References 130

1. Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative dementing illness that affects up to 5% of those over 65 years and rising to >20% of those over 80 (Launer et al., 1999). While the disease itself is not fatal, medical complications associated with AD result in it being termed the fourth largest cause of death in the Western world (after coronary heart disease, cancer, and stroke). AD is characterised by an initial loss of short-term memory, gradually leading to total mental incapacity and full dependence (Bouchard & Rossor, 1996). It was initially reported in 1904 as a form of presenile dementia in a 51-year-old patient, Auguste D. AD is responsible for over 50% of all cases of dementia, although other types of dementia with similar clinical symptoms also exist (Launer et al., 1999). Currently, there are ~350,000 people in the United Kingdom alone with AD, with a cost to the health service, both direct and indirect, of over 2 billion pounds. Because AD initially was defined by its unique pathology of neurofibrillary tangles and neuritic (senile) plaques, the disease can only be diagnosed definitively at the post-mortem stage (Dickson and Goedert). While a majority of AD cases (>95%) are termed sporadic (i.e., have no direct genetic basis), the remainder have been associated with specific gene mutations. These mutations have been identified in both the amyloid precursor protein (APP) (Levy and Goate) and in the presenilin (PS) proteins (3.4 and 4.5). In addition, a number of genetic risk factors have been identified. While these are not an absolute requirement, they act to increase the likelihood of a person developing the disease (Section 4.6).

While there are many components contained within the neuritic plaques of AD brains (which are a general accumulation of cell debris following neuronal cell death), early studies identified a key role for a 40°42 amino acid peptide (Glenner and Masters). This was termed the amyloid (A) peptide because of the -pleated sheet amyloidogenic structure of the aggregated peptide, as detected by Congo red and thioflavin-S staining. The A peptides, which are 3°4 kDa in length, are the building blocks of both the amyloid fibrils in neuritic plaques, in addition to the vascular deposits that accumulate in the brains of patients with AD. A is itself derived from the proteolytic processing of one or more isoforms of the APP (Kang et al., 1987). The isoforms of APP are Type I transmembrane sialoglycoproteins that are encoded for by a single gene on chromosome 21 that contains 19 exons (Goate et al., 1991). The protein exists as 3 primary isoforms: APP695, APP751, and APP770 (the numbers referring to the number of amino acids in the protein). Both APP751 and APP770 contain the 56 amino acid Kunitz protease inhibitor (KPI) domain, which is encoded on exon 7. In addition, APP770 contains a 19 amino acid insert that codes for an OX-2 domain (Fig. 1; Kitaguchi; Ponte and Tanzi). In addition, there is a splice variant, which lacks exon 15, termed L-APP (Pangalos et al., 1995a). There are also two amyloid precursor-like proteins (APLP1 and 2), which have similar extracellular and intracellular domains to APP, but do not contain the 42 amino acid A region (Wasco and Wasco).


Fig. 1. Potential APP processing pathways by the - or /-secretase pathways. The locations of the KPI and OX-2 domains are indicated

2. Amyloid precursor protein function

APP has been proposed to serve as a multifunctional protein that mediates both cell adhesion and neurite outgrowth. Although these two functions are intricately linked and a large number of cell adhesion molecules (CAMs) have been reported to exhibit neuritogenic properties (Doherty et al., 1991), a distinct role for APP as a neurotrophic agent that activates cell-surface receptors to stimulate neurite outgrowth has also been proposed.

2.1. Cell adhesion

The expression of APP as a membrane-bound glycoprotein led to the initial suggestion that it may play a potential role in the mediation of cell adhesion. This suggestion was further fuelled by the irregular punctate-staining pattern of APP on the neuronal cell surface, which is similar to the staining patterns of other CAMs (Shivers et al., 1988), and also by its synaptic localisation (Schubert and Storey). There are reports of two pools of APP within the cell membrane, one with a rapid half-life that gives rise to APPs and the other with a much slower turnover rate that may be responsible for the adhesive properties of the protein (Storey et al., 1999). Initial studies demonstrated that a nerve growth factor (NGF)- or fibroblast growth factor-induced increase in APP expression increases the adhesive strength of PC12 cells to a collagen substrate (Schubert et al., 1989). In addition, the treatment of neuronal cells with heparin, which reduces the strength of their substrate interaction, results in a significant reflex increase in APP mRNA, which has been proposed as a potential compensatory mechanism (Octave et al., 1989). Subsequent studies demonstrated that Fab' fragments of anti-APP antisera can inhibit both cell-cell and cell-substrate adhesion (Breen and Chen), and the down-regulation of cellular APP expression using an antisense strategy also reduces the strength of cell-substrate adhesion (Coulson et al., 1997). Furthermore, an overexpression of the protein in Drosophila results in a blistered wing phenotype, which is suggestive of an alteration in cell-cell adhesion in the dorsal and ventral epithelial cell layers during development (Fossgreen et al., 1998).

In keeping with its proposed role as a mediator of cell-substrate adhesion, APP has been demonstrated to interact with a number of elements of the extracellular matrix. These include collagens I and IV (Breen and Beher), laminin (Multhaup and Kibbey), fibronectin (Narindrasorasak et al., 1995), heparan sulfate proteoglycans (HSPGs) (Narindrasorasak and Coulson), and glycosaminoglycans (Multhaup, 1994). It has also been proposed to play a role as an integral component of the extracellular matrix (Klier et al., 1990). In astrocytes, the cell surface expression of APP co-localises with the 11 integrin at distinct points of contact with the extracellular matrix (Yamazaki et al., 1997). It is not known, however, if APP binds directly with the integrins or is co-localised in focal adhesion points in which the cell interacts with elements of the extracellular matrix. The secreted APPs can also bind to specific proteins on the cell surface, with this interaction, at least in part, being responsible for the adhesion-mediated neuritotropic properties of the protein (Ninomiya et al., 1994).

The individual isoforms of APP exhibit different adhesive characteristics. Using recombinant protein in a binding assay, APP695 was demonstrated to have a lower affinity for both fibronectin and entactin than the KPI-containing forms, and also had a significantly lower capacity for binding to collagen IV (Narindrasorasak et al., 1995). A similar trend was observed with cells overexpressing the APP751 isoform, which have a greater adhesive strength to collagen IV than cells expressing APP695 (Gillian et al., 1997) and which have a greater potential to stimulate neurite outgrowth in a co-culture system (Qiu et al., 1995).

The heparin-binding capacity of APP has been examined in detail, as this may play a key role in the adhesion-mediated neuritogenic properties of the protein (Williamson et al., 1995). At least four binding domains have been identified on the APP695 protein at amino acids 96°119 (H-I), 131°166 (H-II), 316°346 (H-III), and 382°447 (H-IV) (Small; Clarris and Mok; Fig. 2). While the heparin-binding properties of APP provide a mechanism by which the protein interacts with the HSPG elements of the extracellular matrix (Small et al., 1996a), it may also mediate its binding to other components, such as collagen (Breen and Caceres) and glypican (Williamson et al., 1996). A potential heparin-binding site has also been identified within the A region of the protein. This may play a key role in the stimulation of amyloid deposition and the accumulation of HSPG, which is an early event in plaque formation (Snow and Maresh). HSPG can potentiate the neurotoxic effect of the A25°35 fragment, either by altering its aggregation state (Woods and Castillo) or by serving as a potential cell surface receptor for the binding of A fibrils (Schulz et al., 1998). Furthermore, the heparin-binding domain of the A peptide is identical to the microglial-activating domain, suggesting that A stimulation of microglial cells may be a heparin-dependent process (Giulian et al., 1996).


Fig. 2. Schematic diagram of the APP functional domains

In addition to the parent protein, the A peptide may also exhibit adhesive properties. Both A and the C-terminal fragment (CTF; CT105/C100) have been demonstrated to interact with elements of the extracellular matrix, including laminin and fibronectin, to provide a permissive substrate along which neurite outgrowth from spinal cord explants may occur (Ghiso and Koo). This may help to provide an explanation for the neurotrophic actions of low concentrations of A that were originally reported (Whitson and Yankner). However, the stimulation of the activities of the tyrosine kinase, phosphatidylinositol (PI)3 kinase, protein kinase C (PKC), and phospholipase (PL)A2 enzymes by the peptide may also explain some of the physiological activities of low concentrations of A (Luo; Luo; Luo and Lehtonen).

The post-translational modifications of proteins play a key role in determining both their processing and their adhesive properties (Breen et al., 1998). APP can form the core protein of a chondroitin sulfate proteoglycan (Shioi et al., 1992), which is termed appican (Shioi et al., 1996), and it may also exist as an HSPG (Schubert et al., 1988). The attachment of chondroitin sulfate chains is restricted to the Ser619 amino acid residue of the L-form of the protein (that lacks exon 15) (Pangalos et al., 1995a). The expression of appican, which can exist in either a membrane-bound or a secreted protein (Shioi et al., 1993), is restricted to neural cells (Pangalos and Shioi), although the secreted appican may contain the complete amyloidogenic sequence, suggesting an altered processing pathway of the proteoglycan form of the APP (Salinero et al., 1998). The presence of the chondroitin sulfate side chain is important for the adhesive function of APP, as appican demonstrates an increased adhesive potential when compared with the non-chondroitin sulfate proteoglycan form of APP (Pangalos et al., 1996), and the secreted form of appican can also interact with elements of the extracellular matrix in order to promote the adhesion of neural cells (Wu et al., 1997).

While the properties of adhesion molecules have been well-characterised using in vitro systems, their role in the CNS in vivo is less clear. It is proposed, however, that they may play a key role in synaptic plasticity associated with memory and learning (Breen et al., 1998). By altering the adhesive potential of cells, the strength of synaptic connections may be modified, resulting in the potential to alter the existing synaptic connections or even generate new attachments. Because of its adhesive properties, as well as its neuritogenic properties, APP has been proposed to play a role in the modulation of synaptic plasticity (Sisodia & Gallagher, 1998). Indirect evidence for such a role has been provided by reports of a marked increase in APP levels in rats raised in an enriched environment when compared with those in impoverished surroundings (Huber et al., 1997). Early experiments demonstrated that the intraventricular infusion of antibodies directed against the extracellular domain of APP results in an impairment of the acquisition of a passive-avoidance memory task (Doyle et al., 1990). This effect is similar to that reported for other CAMs (Doyle; Scholey and Arami).

Although antibody-intervention studies have provided an indication of the potential functional role of a protein, the possibility exists that the antibody-APP complex may actually act to prevent the action(s) of adjacent cell-surface glycoproteins. Therefore, studies have been carried out to investigate a positive role for APP (rather than a negative role for anti-APP antibodies). Initial experiments were carried out using a 17-mer peptide (containing the RERMS pentapeptide), corresponding to a proposed "active site" of APP that is within a small domain just C-terminal to the KPI insertion site (Fig. 2). Intraventricular infusion of this peptide increases the synaptic density in the frontoparietal cortex, with an associated increase in memory retention (Roch et al., 1994). More recent studies have characterised the role of APP in memory in more detail by the intraventricular infusion of recombinant protein. Both APP695 and APP751 can display nootropic properties, as well as overcoming scopolamine-induced amnesia. In particular, low doses of the protein (0.5°5.0 pg) improved performance in both a go/no-go visual discrimination task and an object recognition task, although higher doses (>5.0 pg) are required to overcome the scopolamine-induced amnesia (Meziane et al., 1998).

APP may also play a role in long-term potentiation (LTP), an electrophysiological correlate of memory and learning (Moser et al., 1998). The induction of LTP in vivo results in an increase in the secretion of APPs in a time-dependent manner, and this can be blocked by pretreatment with either a protease inhibitor or the N-methyl--aspartate antagonist AP5 (Fazeli et al., 1994). Pretreatment of hippocampal slices with APPs produces an alteration in the electrophysiological characteristics of both LTP and long-term depression, further supporting a role for APP in synaptic plasticity (Ishida et al., 1997). Transgenic mice expressing the Swedish mutation of APP (K670N, M671L) display a significant impairment of LTP. This effect is attenuated with age and is accompanied by deficits in spatial memory (Chapman et al., 1999). These effects, however, were not associated with any marked reduction in synapse number or evidence of cell death. This suggests that the mutations in APP, with the associated increase in A generation and decrease in APPs, may impair its ability to modulate synaptic plasticity. These studies have been supported by in vitro studies in which both the A peptide and the CTF (CT105) shorten the duration of LTP induction and the amplitude of excitatory postsynaptic potentials, and therefore, may contribute to the cognitive deficits associated with AD (Cullen; Cullen and Lambert).

The effects of alterations in the expression levels of APP on memory and learning have also been investigated using transgenic mouse models. A moderate increase in APP expression in transgenic mice results in an increase in synaptophysin-immunoreactive synaptic connections (Mucke et al., 1994), but a significant increase in expression of either the full-length form of the protein or the C100 region actually inhibits learning performance at 10 months of age (Hsiao and BergerSweeney). Consistent with this finding are the results from APP knock-out mice or mice containing a shortened form of the protein APP (/), which do not exhibit marked changes in behaviour, although there are subtle changes in locomotor activity, cognitive ability, and LTP (Zheng; Perez; Tremml and Dawson). It is not clear whether these effects are associated with developmental changes due to APP deficiency or to the absence of the protein in the mature brain. There is no evidence, however, of any neuronal loss in the brains of adult APP knock-out mice (Phinney et al., 1999), although there are some changes in neuronal morphology and synaptic efficiency (Seabrook et al., 1999). These studies have been complicated by the potential compensatory effects of other glycoproteins that exhibit similar functional properties to those of APP. In particular, the APP-like proteins APLP1 and APLP2 may counterbalance the changes in APP expression (Wasco and Sandbrink). However, over 80% of animals that are null for both APP and APLP-2 died within the first week after birth, suggesting that while APLP-2 and APP may have similar functions and can substitute for each other, the proteins play a key role in the developmental process (VonKoch et al., 1997). The generation of inducible knock-outs, when the animals are allowed to develop normally and the APP then turned off, will provide a useful model system with which to separate out the developmental from the plastic functions of the protein.

2.2. Neurotrophic actions of amyloid precursor protein

Although both soluble and membrane-bound APP influence adhesion-mediated neurite outgrowth, the soluble form of the protein (APPs) has distinct neurotrophic and neuroprotective properties. The generation of APPs and A are mutually exclusive (Fig. 1), and an increase in A associated with AD with a parallel decrease in APPs generation may render the cells more vulnerable to the actions of other neurotoxins. This may ultimately result in the precipitous nerve cell death that accompanies the later stages of the disease.

A primary role for APPs is as a neuroprotective agent that acts to stabilise intracellular Ca2+ levels. The treatment of cells with APPs results in a rapid and prolonged decrease in cellular Ca2+ (Mattson et al., 1993). Thus, the protein is considered to attenuate the toxic actions of the A peptide by overcoming the A-associated elevation of free intracellular Ca2+ levels with the associated induction of free radical species (Goodman & Mattson, 1994). The neuroprotective properties of APPs, however, are not limited to modifying the neurotoxic actions of A, and the protein can act as a neuroprotective factor in response to a number of diverse stressful conditions associated with elevations in intracellular Ca2+ levels. Treatment of cerebellar granule cells with glutamate results in an increase in free intracellular Ca2+ with subsequent cell death (Budd & Nicholls, 1996). These actions are significantly attenuated following co-treatment with APPs (Mattson, 1994). Ischaemic damage in vivo, which is largely mediated by chronic glutamate release and receptor stimulation, as well as the elevation of intracellular Ca2+ associated with hypoglycemic damage, is also protected against by the co-infusion of APPs (Mattson and Smithswintosky). A similar neuroprotective effect can be observed in vivo, as APP-deficient mice are more susceptible to kainate-induced seizures (Steinbach et al., 1998). The neuroprotective effect of APPs, which is N-methyl--aspartate receptor-specific and not observed following activation of -amino-3-hydroxy-5-methyl-isoxazole-4-propionate or kainate receptors, appears to be associated with the activation of charybdotoxin-sensitive K+ channels, leading to a hyperpolarisation of the neurons (Furukawa et al., 1996a). This effect is mediated by the activation of a cyclic GMP (cGMP)-mediated pathway and can be blocked by inhibitors of a cGMP-dependent kinase and mimicked by nonhydrolysable cGMP analogues (Barger and Furukawa). The characteristics of the induction of long-term depression in hippocampal slices and the frequency of spontaneous postsynaptic currents in the Xenopus neuromuscular junction can also be influenced by the APP-mediated stimulation of cGMP levels. These data provide further evidence for an interaction between APPs and guanylate cyclase (Ishida and Morimoto).

APPs also plays a key role as a neurotrophic agent to stimulate neuronal cell differentiation and neurite outgrowth. Transfection of an APP-null neural cell with APP cDNA results in an increase in neurite outgrowth, and this property has been localised to an RERMS peptapeptide (amino acids 328°332). Furthermore, the binding of a larger peptide (Ala319 to Met335) to cell membrane preparations is both saturable and specific, suggesting that APPs mediates its effects by a receptor-mediated mechanism (Jin and Ohsawa). An active domain has also been reported within amino acids 591°612 within the A peptide region. This domain is present in APPs, but not in APPs, suggesting that the alternative processing of APP by specific secretases may influence APPs function (Furukawa et al., 1996b). At low concentrations, APPs can also potentiate the actions of NGF by the activation of the extracellular signal-regulated kinases ERK-1 and -2 via a PI3 kinase pathway (Wallace and Wallace). In addition, there is an increase in the affinity of the p75 low-affinity NGF receptor and a potentiation of the trkA tyrosine kinase enzyme (Akar & Wallace, 1998). As these agents have also been demonstrated to modulate APP expression and APPs generation, there exists a complex relationship between the expression and function of the protein. Furthermore, although the exact mechanisms underlying the physiological activities of APPs are not clearly understood, the evidence available suggests that the protein may interact with a cell-surface receptor to mediate its biological effects.

2.3. Amyloid precursor protein interaction with membrane-bound proteins

The membrane-bound form of APP has also been proposed to modulate cellular activity, potentially by an interaction with elements of a second messenger system pathway. Initial studies suggested an interaction between the C-terminal domain of APP and the Go protein, with the subsequent binding of GTP-S to Go (Nishimoto et al., 1993). This binding could be inhibited by the pretreatment of Go with GTP-S. The binding of the 22C11 antibody, which recognises the N-terminal of APP, resulted in an increase in GTP-S binding and an increase in GTPase turnover. This effect could be blocked by an antibody directed against the intracellular C-terminal of APP, which may mediate APP-Go protein interaction (Okamoto et al., 1995). More recent studies, however, have reported that the interaction of APP with Go results in an inhibition of the high-affinity Go GTPase activity, with this effect being potentiated by treatment of cell membranes with the 22C11 antibody (Brouillet et al., 1999). The apparent anomaly between these results may reflect the differences between the two experimental systems used. The first experiments were carried out using reconstituted phospholipid vesicles, while the more recent studies were carried out using whole cell preparations. This suggests that other membrane-bound proteins may also influence APP-Go interaction. Subsequent events in the APP-Go pathway include the activation of mitogen-activated kinase enzymes and the phosphorylation of specific proteins (Murayama et al., 1996).

While the function of the APP-Go complex has not been clarified, the induction of apoptosis and cell death in cells expressing familial AD (FAD) mutations of APP at amino acid V642 (Yamatsuji et al., 1996b) may occur via a G-protein-mediated mechanism. Go appears to be constitutively activated in cells expressing mutant APP, and treatment with pertussis toxin, an inhibitor of G-protein function, or co-transfection of the cells with an inactive form of Go greatly reduced the occurrence of apoptotic cell death (Yamatsuji et al., 1996a). The Go-subunit involved appears to be the G component, as overexpression of cDNA coding for G22 also induced DNA fragmentation and cell death, thus also implicating this protein in the apoptotic pathway (Giambarella et al., 1997b). FAD mutations of APP also inhibit the activity of the cyclic AMP (cAMP) response element by a Go-dependent, but adenylate cyclase-independent, mechanism following the binding of the mutant APP to the C-terminus of Go. This suggests that the APP mutants actually may demonstrate a gain-of-function (Ikezu and Giambarella).

In addition to Go, a number of other cellular proteins have been reported to interact with the C-terminal of APP. APP-BP1 is a 59 kDa protein homologous to the Arabidopsis AXR1 gene that plays a role in signal transduction and is related to the ubiquitin-activating enzyme E1 (Chow et al., 1996). APP also interacts with the neuronal protein Fe65, which is a homologue of protein X11 (Fig. 3).


Fig. 3. Schematic diagram of the interaction of the cytoplasmic tail of APP and the LRP with a multimeric protein complex

Recent studies have identified a 130 kDa protein that binds to residues 645°694 in the intracellular portion of APP and that co-immunoprecipitates with APP (Watanabe et al., 1999). This protein is homologous to the UV-damaged DNA-binding protein (UV-DDP) that plays a role in DNA repair. Although the role of the APP/UV-DDP interaction remains unclear, this may serve as a signal transduction mechanism responsible for the regulation of gene transcription, as UV-DDP has been proposed to translocate between the cytoplasm and the nucleus. APP has also been demonstrated to bind to the PS proteins within the membrane (Xia et al., 1997) (Section 3.4). Although the PS proteins generally have been identified as elements of the endoplasmic reticulum (ER) and cis-Golgi (Culvenor et al., 1997), there is some evidence that they may also exist at the level of the cell surface and play a role in the processes of secretion and endocytosis (Efthimiopoulos et al., 1998). They may also bind to APP on an opposing cell in order to mediate cell adhesion (Dewji & Singer, 1997). This trans-binding of the PS proteins and APP results in a transient increase in protein tyrosine kinase activity and protein phosphorylation, and this PS:APP interaction may play a role in intracellular signaling (Dewji & Singer, 1998). Intriguingly, recent studies have proposed that PS1, in fact, may exhibit -secretase activity, and this may also explain the PS-APP interaction at the level of the Golgi (DeStrooper and Wolfe).

Because of both its adhesive and neurotrophic properties, APP is likely to play a role in the process of neuronal development. While there are no overt changes in APP knock-out animals, hippocampal cells cultured from these animals exhibit reduced viability and defective neurite outgrowth (Perez et al., 1997). This deficit, however, can be rescued by co-culturing the cells with astrocytes derived from control animals, suggesting that APP plays a key role in the developmental process. APP knock-out mice also demonstrate an increased sensitivity to the actions of the excitotoxin glutamate. However, although the animals are more prone to kainic acid-induced seizures, there is no evidence of increased cell death or apoptosis (Steinbach et al., 1998). However, further studies using inducible knock-out animals are required to fully understand the function(s) of APP.

3. Amyloid precursor protein processing

Two alternative pathways that are mutually exclusive serve to process APP. The primary pathway results from the cleavage at Lys16 within the A region of the protein by the -secretase protease enzyme. This results in the generation of the soluble APPs that displays neurotrophic and neuroprotective properties. Alternatively, it can be cleaved by the - and -secretases to generate the 40/42 amino acid A peptide (Busciglio and Mills). The major species of A generated under normal circumstances is the 40 amino acid A40 form (Haass and Seubert). However, in AD, there is an increase in the A42 peptide that is more amyloidogenic and acts as a seed for amyloid deposition (Pike; Borchelt and Lemere). A42 is also the major A component of the amyloid plaques (Roher and Iwatsubo). The choice of the pathway by which APP is processed is influenced by a large number of factors that are both extra- and intracellular. Furthermore, the processing mechanisms may be cell-, tissue-, or species-specific.

APP trafficking in nonpolarised cells indicates that the protein is delivered to the cell surface via a constitutive biosynthetic pathway, where it can be cleaved by -secretase and secreted as APPs. Alternatively, it can be internalised by endocytosis and eventually degraded (Haass; Nordstedt and Koo). In polarised cells, however, alternative splicing of the protein is particularly important in determining the fate of the protein, with exon 15 (L-APP) playing a pivotal role in this process. In canine kidney cells, APP is sorted basolaterally, while cells transfected with L-APP677 expressed this isoform both apically and basolaterally (Hartmann et al., 1996).

In both mouse teratocarcinoma cells (P19) and human embryonic kidney cells (HEK293), the generation of APPs by -secretase cleavage is reduced by the expression of the KPI containing isoforms of APP, with a concomitant increase in A. Thus, in human brain and in animal models of AD, the amount of KPI-containing APP produced may be a key factor in influencing the deposition of A (Ho et al., 1996). The KPI-containing isoforms are expressed both in the CNS and in the peripheral tissues, whereas APP695 is expressed almost exclusively in the brain. During normal aging, APP751 levels increase in parallel with the age-associated loss of neurons (Tanaka and Tanaka) and the ratio of APP751/APP695 mRNA is correlated positively with plaque density in the brains of AD and control patients (Johnson et al., 1990).

While trace amounts of A peptide have been detected as part of the normal cellular metabolism of APP (Haass and Shoji), an increase in the production of the peptide and its subsequent deposition as insoluble amyloid plaques may represent the key pathological event that triggers the disease process (Hardy and Selkoe). As such, any manipulation that diminishes the production of A may be a potential therapeutic target (Mills and Schenck). In non-neuronal cells, the secreted APPs fragments are generated primarily via the -secretase pathway, with a minority being produced by the /-secretase route (Fig. 1), primarily in the endosomal/lysosomal (E/L) pathway (Cole and Golde). There is some evidence, however, that some full-length APP can also be secreted (Vassilacopoulou and Tezapsidis). While the -secretase has not been identified, it is thought to be localised either in the late Golgi or in caveolae within the plasma membrane ( Mills & Reiner, 1999; Section 3.2).

APP has also been associated with ubiquitin in the E/L compartments in AD. While ubiquitin normally plays a role in the targeting of proteins to the proteasome, in stress-related conditions where there is an elevation of APP and its fragments, ubiquitin may start to play a role in the processing or trafficking of APP to the E/L compartment. Temperature-block studies of metabolically labelled proteins suggested that vesicle budding and trafficking of APP to the cell surface are not an absolute requirement for the generation of A in Neuro 2A rat neuroblastoma cells (Xu et al., 1997). This implies that the - and -secretase cleavage can occur within the ER or trans-Golgi network (TGN) (Cook and Hartmann). Although the -secretase pathway appears to play a key role in the processing of APP in neuronal cells (Turner and Tienari), there is no conclusive evidence that deciphers the exact location of these secretase pathways in any cell type. While there is evidence that the cleavage occurs in the late endosomal compartment, with the cleavage occurring in the early endosomes (Peraus et al., 1997), other studies suggest that the cleavage occurs prior to the cleavage (Anderson and Paganetti). The exact subcellular location of APP cleavage may differ between species, and this factor may help to explain why AD is a human-specific disease (LeBlanc & Goodyer, 1999). While the -secretase enzyme has not been identified yet, its actions, which may be associated with multiple proteases, are determined by the location of the APP within the plasma membrane (Murphy et al., 1999). Furthermore, the -secretases, which generate A40 and A42 may be distinct enzymes, with the -40 secretase being a cysteine protease and -42 being a serine protease (Klafki; Citron and FigueiredoPereira), with the generation of A40 and A42 occurring within different compartments of the cell. It has been proposed that A40 is generated in the TGN, while A42 is produced both within the ER and the TGN with the A generated in the TGN being localised in two distinct pools (Greenfield et al., 1999).

3.1. Intracellular transport of amyloid precursor protein

In an attempt to decipher the pathways and organelles involved in APP catabolism, studies have examined the motifs present on APP that appear to play important roles in the localisation of the protein. These studies have confirmed that APP uses a specific intracellular route that targets proteins to the E/L system, although, to date, the full role of this organellar system is unclear (Nordstedt et al., 1993).

There are a number of classes of transport vesicles, each of which plays a specific role in intracellular protein transport. These lipid vesicles contain a specialised protein coat and bud-off from membranes to transport proteins between organelles within the cell. There are three main classes of coated vesicles. Coatomer-coated vesicles mediate transport between the ER and the Golgi. Clathrin-coated vesicles (CCVs) mediate the transport of transmembrane proteins, such as APP and the low-density lipoprotein (LDL) receptor, between the Golgi and the plasma membrane. The third class of vesicles was originally identified as invaginations at the level of the plasma membrane. These caveolae are thought to play a major role in the recycling of proteins from the cell membrane, probably to the E/L compartments.

The presence of both full-length APP and associated peptide fragments in the CCVs suggests that the secretory cleavage of APP occurs in a pre-CCV compartment (Liu and Wu). In fact, it is possible that internalised caveolae and CCVs may be targeted to a common endosomal pool (Simons & Ikonen, 1997). In this model of APP processing, since cytoplasmic APP has been shown to be enriched in lysosomes (Haass et al., 1992a), it is likely that the -secretase cleavage occurs first in the caveolae, with the remaining intact APP being cleared from the cell surface by the clathrin-coated pits and targeted to the endosomes and lysosomes for proteolytic processing (Koo and Yamazaki). In agreement with this hypothesis, the activation of PKC, a well-established component of caveolae, which is known to stimulate the secretion of APP, inhibits caveolae internalisation (potocytosis) (Lisanti and Smart). This suggests that PKC activation may prolong the time spent by APP at the level of the cell surface, thus maintaining APP in close contact with the plasma membrane form of -secretase, and may play a key role in the PKC activation of APPs secretion (Section 3.5).

3.2. Caveolae and cholesterol

Caveolae are sphingomyelin/cholesterol-rich membrane domains in which the cholesterol component plays a key structural role (Sargiacomo and Liu). Cholesterol-depleted cells have reduced numbers of caveolae (Anderson; Chang and Anderson) and cholesterol-binding drugs, such as nystatin and filipin, disassemble the membrane coat of caveolae in fibroblast cells (Rothberg et al., 1992).

The homo-oligomeric caveolin proteins that bind cholesterol and glycosphingolipids serve as marker proteins for caveolae (Rothberg and Ikezu). These protein-protein and protein-lipid interactions are thought to be essential for the formation of caveolae (Sargiacomo et al., 1995). Caveolin contains a modular protein domain that directly participates in the recognition of specific consensus motifs within its interacting partners (Couet et al., 1997). Caveolins play a key role in G-protein-coupled signalling by interacting directly with the Gs-subunit (Li et al., 1995) or indirectly via ligand-binding proteins (e.g., muscarinic acetylcholine, -adrenergic, and bradykinin receptors) (Raposo; Raposo; deWeerd and Feron). APP contains a caveolin-binding motif within its cytoplasmic domain, which may explain the internalisation/sequestration of APP into caveolae (Ikezu et al., 1998). The -secretase cleavage product of APPs has been shown to be enriched within caveolae (Bouillot et al., 1996), and the co-expression of APP and caveolin-1 results in the -cleavage of APP at the plasma membrane. These results suggest that caveolae, therefore, play a significant role in the -secretase cleavage pathway of APP (Fig. 4) (Ikezu et al., 1998).


Fig. 4. The proposed role of caveolae in the processing of APP. Increased cellular cholesterol decreases APPs secretion. Decreased cellular cholesterol (by cholesterol-lowering agents) results in a decrease in A generation, with no effect on APPs. These effects suggest a role for caveolae in APP processing

Treatment of cells with cholesterol oxidase results in the appearance of caveolin within the Golgi, suggesting that oxidized or otherwise damaged cholesterol may stimulate the movement of caveolin from the cell surface to the Golgi through the ER/Golgi pathway and that this translocation requires a functional cytoskeleton. Movement in the other direction from the Golgi to the plasma membrane, however, is a microtubule-independent process (Conrad et al., 1995).

While the -secretase-mediated cleavage of APP may occur at the level of the cell surface, suggesting that the protease involved is a membrane-anchored protein (Haass et al., 1992a), the cleavage can also occur intracellularly (Destrooper et al., 1993), and a disintegrin and metalloprotease (ADAM 10) has been proposed as a potential candidate enzyme for this cleavage (Lammich et al., 1999). The activation of caspase enzymes associated with apoptosis has also been proposed to generate A (Gervais et al., 1999). However, the cleavage to generate A occurs only after APP has been modified by O-glycosylation, suggesting that the process takes place within or after the Golgi complex (Tomita et al., 1998). Although this may represent a caveolar-independent pathway, and there are some reports that a specific pool of APP may not be associated with caveolae (Parkin et al., 1997), it may also reflect the intracellular localisation of certain forms of caveolae. No -secretase cleavage could be detected at the level of plasma membrane in the absence of caveolin-1, thus suggesting that caveolae may play a pivotal role in the cycling of APP between the cell surface and intracellular populations of caveolae (Ikezu et al., 1998).

There are several links between cholesterol metabolism and the pathogenesis of AD. In particular, specific allelic forms of apolipoprotein E (ApoE) serve as a genetic risk factor for the development of the disease (Strittmatter et al., 1993). There are three ApoE isoforms (termed E2, E3, and E4), and people who are either homozygous or heterozygous for the E4 allele have an increased susceptibility to AD. Cholesterol modulates certain physical properties of membranes, and the internalisation of ApoE-lipoprotein complexes serves as the primary cellular mechanism for cholesterol uptake (Guillaume et al., 1996). This uptake is mediated by the LDL receptor pathway (Dehouck et al., 1997). ApoE-enriched lipoproteins can bind the A peptide, with the resulting complexes being taken up into primary neurons and astrocytes by the LDL receptor (Beffert et al., 1998). The ApoE2 and ApoE3 alleles appear to bind A with a higher affinity than ApoE4, and therefore, they may play an important role in clearance of the peptide prior to its aggregation into insoluble deposits (Yang et al., 1999). In addition, the LDL receptor-related protein (LRP) receptor (Fig. 3) mediates the uptake of the secreted APPs from the extracellular space (Kounnas et al., 1995). Cholesterol modulates APP processing, with a reduction in the levels of APPs associated with increased cellular cholesterol levels (Bodovitz & Klein, 1996). This has been associated with an increase in the level of both the mature and the immature forms of the APP holoprotein, while there was no apparent effect on A production (Bodovitz & Klein, 1996). Other studies report, however, that a 70% reduction in the cellular cholesterol by lovastatin and methyl--cyclodextrin eliminates the production of A without affecting the secretion of APPs (Simons et al., 1998), and increased cholesterol may be associated with the "seeding" of amyloid deposits by A (Mizuno et al., 1999). This effect may be due to a preferential interference with the -cleavage pathway over the -cleavage. Dietary cholesterol may also modulate the processing of APP, with an increased cholesterol intake leading to a decreased secretion of APPs, A40, and A42. This only occurs in the presence of ApoE, suggesting that the effect of cholesterol on APP processing is an ApoE-dependent event (Howland et al., 1998). Altered dietary cholesterol did not appear to have any effect on the levels of the full-length holoprotein (Howland et al., 1998). These links between cholesterol and APP, however, may reflect the caveolar localisation of APP (Ikezu et al., 1998), and a neuronal-specific form of caveolin may interact with neuronally expressed APP. Caveolar dysfunction, therefore, would lead to a down-regulation of the -secretase pathway in AD, which may result in an overproduction of the toxic A peptide (Ikezu et al., 1998).

3.3. The role of membrane-bound proteins in amyloid precursor protein processing

APP has two internalisation signals on its cytoplasmic tail, Gly-Tyr-Glu-Asn-Pro-Thr-Tyr (GYENPTY) and Tyr-Thr-Ser-Ile (YTSI), both of which appear to play a role in the lysosomal targeting of the protein (Lai et al., 1995). The cytoplasmic region of the GYENPTY motif interacts with the phosphotyrosine-binding/protein interaction domain of X11 (Borg et al., 1996) and Fe65 (McLoughlin & Miller, 1996) (Fig. 3). Non-neuronal cells require the GYENPTY motif for the endocytosis of cell surface-expressed APP by clathrin-coated pits (Haass and Koo), and this motif is sufficient for subsequent A production. The use of mutation/substitution studies of various motifs and regions of the APP protein, and the resultant pattern of peptide formation, have confirmed that internalisation results in a reduction of the secretory cleavage of APP. This further emphasises the importance of APP re-internalisation in the processing pathway of this protein.

The efficient targeting of APP to lysosomes requires both the YTSI and the GYENPTY motifs, with the Tyr653 residue of the YTSI motif being particularly important for its basolateral expression in polarised cells (Lai et al., 1998). The interaction of X11 or X11 with APP has a significant effect on APP processing, with a decrease in the quantity of APPs, A40, and A42 being recovered from the conditioned medium of HEK 293 cells expressing X11 (Borg et al., 1998). Co-expression of X11 with APP containing the Swedish mutation (APPSwe) resulted in a decrease in the secretion of both A40 and A42 compared with APPSwe expression alone (Borg et al., 1998). Transfection of APPSwe lacking the N-terminal cytoplasmic tail showed no such reduction by X11.

Fe65 interacts with the LRP via its N-terminal tail and also interacts through its carboxyl terminal domain, with the NpxY motif in the cytoplasmic tail of APP (Fiore et al., 1995). Fe65 is also capable of interacting through its WW domain with Mena (the mammalian homologue of enabled), which, in turn, interacts with the cytoskeleton and the CP2/LSF/LBP1 transcription factors to produce a macromolecular complex (see Fig. 3; Russo and Zambrano). APP and LRP can also interact with the mammalian homologue of disabled via the carboxyl terminal NPxY motif (Duilio and Howell), with mammalian homologue of disabled knock-out mice showing abnormal neuroanatomical organisation of the cortical cell layer (Howell et al., 1997b). The KPI-containing isoforms of APP can also interact directly with the extracellular domain of LRP (Kounnas et al., 1995), although these isoforms usually are expressed in very low levels in neurons. The multivalent complex comprising LRP, Fe65, and Mena can modulate the intracellular trafficking of APP. Mutations in the NpxY motif of the cytoplasmic domain result in an increased secretion of APPs, with no effect on A production, suggesting that the two APP processing pathways may exist independently (Jacobsen et al., 1994). This deletion of the NPTY motif, however, may not only impair endocytosis of cell surface APP, but it may also alter its intracellular trafficking by increasing its direct targeting into the endocytic pathway without first reaching the cell surface (Guenette et al., 1996). Preliminary studies have also proposed the possibility of genetic polymorphisms in the Fe65 gene being associated with sporadic AD, with these changes potentially modifying the interaction of the protein with APP (Hu et al., 1998).

A detailed investigation of neuronal APP transport and processing in the rat CNS has revealed that the protein is transported in an anterograde fashion from the cell body to the synaptic sites, with the majority of the APP existing as the APP695 isoform. Only mature, fully glycosylated APP can be transported by this fast axonal transport (McFarlane and Buxbaum), after which it is inserted into the plasma membrane, where it has a rapid turnover rate (Morin et al., 1993). The A region is also essential for the axonal sorting of the protein (Tienari et al., 1996). Synaptosomal studies have revealed that full-length APP in the nerve terminals is included in structures associated with the endocytic pathway, particularly in the multilamellar organelles and the CCVs, with APP being excluded from small synaptic vesicles (Marquez-Sterling et al., 1997). In this dentate gyrus model, full-length APP has been shown to exist inside clathrin-coated synaptic vesicles that are recycled to the early endosomal compartments, where sorting takes place. While a portion of the APP may recycle back to the presynaptic plasma membrane, APP is definitely transported retrogradely to the somatodendritic domain. A portion of this is subsequently directed transcytotically to the somatic surface (Simons and Yamazaki), but delivery to the late E/L compartments where degradation takes place probably also occurs (Marquez-Sterling et al., 1997). However, whether this APP is in the presynaptic terminal or associated with the extracellular space cannot be determined in this model. It has been proposed that it may serve as a ligand that interacts with a postsynaptic receptor (Breen; Furukawa and Gillian).

There are two key pieces of evidence to suggest that the CTFs of APP appear to be the penultimate precursors of the A peptides (Estus and Simons). Firstly, cells and transgenic animals that express the Swedish APP variant secrete high levels of A in parallel with an increase in APP CTFs that contain an N-terminus at the -secretase cleavage site (Thinakaran; Lamb and McPhie). Secondly, neurons from mice that lack the PS1 protein and that fail to secrete A accumulate large quantities of the CTF within the cell (DeStrooper and Naruse). These findings suggest that the accumulation of CTF may itself be toxic (Section 4.9). This hypothesis is backed up by the observation that accumulated CTFs are found in cells that have internalised A42 peptide aggregates. Indeed, several reports point to the toxicity of CTF both in vitro (Kim & Suh, 1996) and in vivo (OsterGranite et al., 1996).

3.4. Presenilins

Mutations in the genes coding for the PS proteins PS1 and PS2 are responsible for a large number of cases of FAD (Sherrington et al., 1995). These are membrane-spanning proteins with 7 transmembrane domains that are located within the ER and the cis Golgi (Culvenor and Nakai). While their exact function remains to be elucidated, they have been proposed to play a role in protein trafficking within the cell (Naruse et al., 1998). In addition, PS may facilitate Notch-mediated target signalling during mammalian embryogenesis (Ray et al., 1999). Indeed, PS1 knock-out mice display abnormalities in body segmentation, in addition to cerebral haemorrhage (Conlon and Wong).

PS1 and 2 mutations serve to modify the processing of APP in a manner that leads to the increased generation of the A42 peptide with a parallel decrease in APPs (Borchelt; Citron and Murayama). These mutations are thought to potentially modulate the trafficking of APP (Weidemann et al., 1997). However, it is still unclear as to whether the effects of mutant PS proteins are due to a direct effect on the proteolytic processing of APP or an indirect effect on its trafficking. Studies with other ER chaperone proteins have demonstrated that mutations of these proteins result in altered APP processing and A production (Yang et al., 1998). Furthermore, it is not clear whether the C- and N-terminal fragments of PS are the active components or whether the full-length PS is the functional moiety. Intriguingly, a recent report has proposed that PS1 itself may be the -secretase enzyme (DeStrooper and Wolfe).

3.5. Protein kinase C

The PKC family is a heterogeneous family of phospholipid-dependent kinases that can be divided into three categories, based on their cofactor requirements. The conventional PKC isoforms (, , and ) require Ca2+, phosphatidylserine, and diacylglycerol (DAG)/phorbol esters as cofactors. Novel PKCs , , , and require only phosphatidylserine and DAG/phorbol esters, while the atypical PKC enzymes and , whose regulation has not been fully deciphered yet, require phosphatidylserine for maximal activity. PKC enzymes contain four functional domains. The C1 domain binds DAG and phorbol esters in all but the atypical PKC enzymes. The C2 domain binds to the acidic phospholipids (and Ca2+ in the conventional PKC enzymes). These C1 and C2 interactions stimulate the transport of PKC to the plasma membrane, where the phosphorylation of cellular proteins occurs following the binding of ATP to the C3 domain, the substrate protein being bound to the C4 domain.

Colchicine sensitivity studies (Nitsch et al., 1993) and the effects of cholera toxin on constitutive versus PKC-induced APP secretion (Efthimiopoulos et al., 1994) suggest that the receptor-activated and constitutive -secretase processing may occur by different mechanisms. This statement is further supported by the observation that whilst both PKC and - were involved in phorbol ester-regulated secretion of APPs from the rat fibroblast 3Y1 cells that were stably overexpressing these isoforms only, PKC was involved in the stimulation of basal APP secretion (Slack and Kinouchi). In the same studies, the PKC isoform showed no such effects. Ionophore studies demonstrated that monensin decreases both the regulated and constitutive secretion of APP, which, in turn, increased the intracellular levels of APP, possibly by upsetting the normal trafficking of the protein within the cell. Whilst ammonium chloride exhibited similar properties, nigericin showed little or no effect on APP processing (Lahiri and Lahiri). Along the same lines, it is interesting that the basal levels of APPs are higher in synaptosomes derived from the cortex and hippocampus of methylazoxymethanol-treated rats, in which PKC is permanently hyperactivated in these brain areas, while synaptosomes derived from other areas in the same animals show similar levels to control rats (Caputi et al., 1997). In A431 cells, activation of the epidermal growth factor (EGF) increases the secretion of APPs through a joint PKC/tyrosine kinase mechanism (Slack et al., 1997). Elevations of intracellular Ca2+ levels in turn may be responsible for the tyrosine kinase-dependent release of APPs (Petryniak et al., 1996). Intracellular cAMP inhibits both the constitutive and the phorbol ester-mediated secretory cleavage of the amyloid precursor protein and, therefore, serves to modulate the PKC pathway (Efthimiopoulos et al., 1996).

The observation that skin fibroblasts from controls, people with Down's syndrome (DS), and patients with a deletion in chromosome 21 show that PKC stimulation of APPs release is inversely proportional to the expression level of the APP holoprotein (Govoni et al., 1996). This PKC-dependent secretory mechanism has been shown to be defective in skin fibroblasts derived from individuals with sporadic AD due to altered levels of PKC (Bergamaschi and Ibarreta), which is one of the major PKC isoforms present in skin fibroblasts, as well as in the brain (Ibarreta et al., 1999). This, in turn, implies a role for these isoforms in the PKC stimulation of APPs release. Studies with benzolactam, a novel PKC activator with improved selectivity for the PKC, -, and - isoforms, demonstrated an enhanced secretion of APP from fibroblasts of AD patients and in PC12 cells (Ibarreta et al., 1999), thus implying an additional role for PKC- (in addition to those previously reported for PKC and PKC). Use of a specific inhibitor of PKC, Go-6976, suggests a partial dependence of PKC on constitutive APPs secretion from human fibroblasts, but a complete dependence of the phorbol ester-mediated PKC stimulation of APPs release (Benussi et al., 1998). The role of PKC is further confirmed by the observation that the proliferative state of the cells also affects their secretion of APPs, with differentiation of rat primary neurons resulting in an increase in basal levels of secretion coincident with the appearance of PKC expression (Salinetti et al., 1996).

Treatment of cells or synaptosomal membrane preparations with phorbol esters has been shown to increase the secretion of APPs (Ibarreta and McLaughlin) and to inhibit the production of A (Koo, 1997). This process is not associated with the direct phosphorylation of APP, as the removal of the cytoplasmic tail of this protein, which is the region of APP likely to be phosphorylated (Ando et al., 1999), had no effect on this phorbol ester-mediated induction of protein secretion. The deletion, however, did result in a significant increase in the basal level of APPs secretion (Koo et al., 1996), possibly by reducing the rate of APP internalisation, thus emphasising the importance of the endocytic pathway in the processing of APP to A (Section 3.3). The PKC-associated increase in APPs generation is not due to an increase in the resident time of APP at the cell surface (Koo, 1997). There are, therefore, two hypotheses that may explain the effects of phorbol esters on APPs secretion: (1) PKC enhances the activity of the -secretase enzyme(s) and/or (2) PKC shuttles APP into the resident compartment of the -secretase.

The observation that the activation of PKC prevents potocytosis (internalisation of caveolae) (Section 3.2), which in turn leads to an increase in the secretion of APPs, would seem to suggest the caveolae as being the potential resident compartment of the -secretase enzyme (Section 3.2). The effect of PKC on the secretion of APPs is also associated with the budding of secretory vesicles from the Golgi network (Xu et al., 1995). Furthermore, there is evidence that PKC may also directly activate the -secretase activity present within the proteasome multicatalytic complex (Marambaud and Marambaud) and that PKC-stimulated APPs secretion may be attenuated by the inhibition of a hydroxamic acid-based inhibitor-sensitive protease (Racchi et al., 1999b). The effect of PKC activation on APPs generation is also influenced by other factors, including the cellular differentiation state, as well as the quantity of APP within the cell (Loffler and Racchi). Decreased cellular APP associated with a deletion in chromosome 21 resulted in an increased response to PKC activation when compared with control fibroblasts. In contrast, there was an attenuation of the response in fibroblasts from DS patients, who have an increased level of APP (Racchi et al., 1999a). An activation of mitogen-activated protein kinase (MAPK) has also been implicated as a PKC effector (DesdouitsMagnen et al., 1998).

3.6. Muscarinic receptors

M1 muscarinic acetylcholine receptors (mAChRs) are thought to be predominantly localised postsynaptically, whereas a population of the M2 mAChR autoreceptors exist presynaptically and regulate acetylcholine release (Hulme et al., 1990). Reduced numbers of M2 receptors in AD brains have been reported in numerous studies (Svensson and Greenamyre). This is consistent with these receptors being present on degenerating cholinergic nerve terminals. However, M2 receptors have also been reported to exist postsynaptically (Dawson et al., 1990), with this expression potentially masking even greater reductions in the presynaptic M2 receptor levels. The levels of M1 receptor seem to remain unchanged in AD, although there is some evidence to suggest that the interactions between the M1 receptor with its associated G-proteins, and the subsequent activation of phosphoinositide signaling, may be impaired in AD (Ferraridileo and Jope).

Muscarinic receptor activation has both PKC-associated and tyrosine phosphorylation-dependent components (Slack et al., 1995). The M1, M3, and M5 mAChRs are associated with the phosphoinositide cascade and stimulate PI hydrolysis through the activation of PLC, which in turn can stimulate PKC, and PLA2, with a subsequent increase in APPs secretion (Nitsch; Emmerling and Wolf). The stimulation of other PKC-coupled neurotransmitter receptors (glutamatergic and serotonergic subtypes) also increases the secretion of APPs (Lee and Nitsch). These observations point to the existence of a system that should be capable of regulating APP catabolism by both PKC-dependent and PKC-independent mechanisms, with the MAPK signalling pathway satisfying both of these conditions (Cobb and Malarkey).

The tyrosine phosphorylation component of the muscarinic effect is mediated via an elevation of intracellular Ca2+, suggesting that this increase may mediate the tyrosine phosphorylation-dependent release of APPs in response to carbachol (Petryniak et al., 1996). MAPK enzymes, also described as ERKs, are the terminal enzymes in a three-level kinase cascade involving the sequential activation of raf, MAPK, and ERK (Pelech & Charest, 1996). It is worth noting that PS1 (Section 4.5) has also been shown to have a consensus sequence for ERK-dependent phosphorylation, and may serve as a substrate for PKC (Seeger and Walter). Activation of the MAPK pathway was found to be necessary for the regulation of the secretory processing of APP (Mills et al., 1997).

The activation of G-protein-coupled receptors can result in the increased tyrosine phosphorylation of the paxillin protein. This protein is involved in the formation of focal adhesions, which are complexes of cytoskeletal-associated proteins that are localised to the integrin-extracellular matrix-binding sites (Jockusch et al., 1995). APPs release may occur in conjunction with a cytoskeletal reorganisation associated with the tyrosine phosphorylation of paxillin (Zachary and Rankin). This hypothesis is supported by a direct relationship between the strength of cell adherence and the release of APPs (Monning et al., 1995), and is consistent with the function of APP as a mediator of cell adhesion (Breen and Gillian).

Since muscarinic receptor-associated activation of PKC has been shown to reduce the production of A, a decrease in the density of the mAChR may also attenuate the release of APPs. It is also interesting that the mAChR subtypes, which stimulate the secretion of APPs, are enriched in those brain areas that are most affected by AD. This has led to the hypothesis that impaired signalling through cortical/hippocampal M1/M3 mAChR may play a role in the pathological processing of APP (Robner et al., 1998). The increase in APPs secretion by phorbol esters, and the associated decrease in A generation, can be observed with all of the APP isoforms (Buxbaum and Caporaso). However, these effects were seen to be both species- and cell type-specific, indicating that the use of PKC activators alone may not be a viable strategy to reduce human brain A levels (LeBlanc et al., 1998). However, the treatment of AD with M1-specific agonists may be beneficial, although to date, selective agonists have been difficult to develop. This lack of specificity may result in a stimulation of the presynaptic M2 receptors, with a consequent decrease in neocortical acetylcholine release.

3.7. Growth factors

NGF has been shown to increase the level of total APP mRNA, with a particular elevation of the APP695 isoform and a parallel up-regulation of APPs secretion (Rossner et al., 1998). This effect was originally reported in PC12 cells (Fukuyama et al., 1993), in mouse neuronal cells in culture (Ohyagi & Tabira, 1993), and in hippocampal explant cultures (Clarris et al., 1994). While antibodies against NGF block this effect, the addition of exogenous APP mimics it, but only in the presence of heparin sulfate proteoglycans (Ohyagi & Tabira, 1993). In NGF-deprived rat superior cervical ganglion cells and primary dissociated cultures of sympathetic neurons, neuronal degeneration has been associated with a decrease in APP695 and an increase in APP751/APP770 (Smith et al., 1993). The effect of NGF on A generation has not been clarified, although maintenance of PC12 cells in serum-free medium in the absence of NGF results in an increase in the generation of an amyloidogenic CTF of APP (Baskin et al., 1991). NGF is believed to stimulate APPs production via the p75NTR receptor subunit, the activation of sphingomyelinase, and the subsequent generation of ceramide and the activation of nuclear factor B (NFB). Activation of the TrkA receptor results in a suppression of APP mRNA expression via the p21Ras-activated signalling pathways involving MAPKs and PI3 kinase, whilst there is a concomitant increase in the secretory processing via the PLC transduction cascade (Robner et al., 1998). Other growth factors, such as EGF, also stimulate APPs release, although the actions of EGF are mediated via PKC and phosphoinositide-specific PLC pathways (Slack et al., 1997).

3.8. Thrombin

Thrombin is a multifunctional serine protease that has been detected in amyloid plaques and has also been reported to be capable of cleaving APP at a site just upstream of the amino-terminus of the A domain (Davis-Salinas et al., 1994). While this led to the suggestion that thrombin may play a role in the generation of the A peptide, subsequent studies reported that high concentrations of thrombin actually increased the generation of APPs, although at low concentrations, it actually acts to break down APPs. The altered proteolysis of APPs may result in the abolition of the neurotrophic/neuroprotective properties of APPs, and therefore, thrombin may be indirectly involved in the pathogenesis of AD through this proteolytic activity (Davis-Salinas et al., 1994).

3.9. The inflammatory response

There is increasing evidence that plaque-associated activated microglia and microglial-derived cytokines are important pathogenic factors in the progression of the neuropathological changes associated with AD. In particular, they are thought to act to potentiate the cell damage in the early stages of the disease, and this has led to the suggestion that the AD pathology may have a multi-factorial origin. In particular, the activated microglial cells surrounding the plaque core may play a pivotal role in the neurodegenerative process. While under normal conditions microglial cells are dormant, in AD, they express cell-surface antigens that are characteristic of activated cells in the chronic inflammatory state (Akiyama et al., 1994). This activation may be due in part to the binding or internalisation of microaggregates of the A peptide in an effort to clear the initial depositions of the aggregated peptide (Giulian and Paresce). Furthermore, A has been discovered to bind to the receptor for advanced glycation end products (RAGE) present on the surface of microglial cells (Yan et al., 1996). The presence of other glycated proteins in the AD pathological lesions may also play a role in microglial activation by RAGE (Ledesma and Vitek), and inhibitors of advanced glycation (e.g., tenilsetam) have demonstrated some evidence of cognitive enhancement in patients with AD (Munch et al., 1994).

The microglial cells, however, are associated with the mature plaques seen in the later stages of neurodegeneration rather than with the earlier diffuse plaques, suggesting that their activation is not an early event in the development of the disease pathology (Mackenzie et al., 1995). While activated microglia may also play a key role in the increased generation of the A peptide from APP (Schaffer et al., 1993), these cells have also been reported to take up A by endocytosis and to degrade the peptide by a metalloprotease, which degrades soluble peptide prior to polymerisation (Paresce and Mentlein). This appears to be a saturable process, which may be overwhelmed by large quantities of A, similar to those produced in AD (Paresce et al., 1997).

Astrocytes can also be activated by the microglial-derived interleukin (IL)-1 to generate the acute-phase protein 1-antichymotrypsin (Kanemaru et al., 1996), in addition to additional cytokines and complement proteins (Mrak et al., 1995). Furthermore, the buildup of proteoglycans that is observed in AD brains (Small et al., 1996b) may play a role in the development of the inflammatory response (Leveugle & Fillit, 1994).

IL-1, which is produced by activated microglial cells, has numerous actions within the CNS that may contribute to the neurodegeneration associated with AD. It up-regulates the expression of APP in neuronal cells both in vivo (Brugg et al., 1995) and in vitro (Buxbaum and Rogers), and this may give rise to an increase in the generation of the A peptide. There is also a positive feedback loop, with the A peptide further stimulating the production of both IL-1 and IL-6 by activated astroglial cells (Delbo and Lorton). IL production is probably an early event in the disease progression, as raised IL-6 levels have been detected in the immature diffuse senile plaques (Hull et al., 1996). This acts to increase neuronal intracellular calcium levels (Barger & Van Eldik, 1992) and therefore, may potentiate the neurotoxic effects of the A peptide, which also raises intracellular calcium (Cotman et al., 1992).

Transforming growth factor (TGF)- is a member of the cytokine family, produced primarily by microglia in the CNS, that plays a role in the control of the inflammatory response. TGF- is expressed following a variety of insults in the brain, including AD-associated cell death (Flanders et al., 1995). It acts to increase both APP expression (Gray & Patel, 1993) and A peptide generation and accumulation, and it may play a role in the development of AD pathology (Harris-White et al., 1998). A similar effect can be observed with prostaglandin E2, which exerts its actions by the activation of protein kinase A (PKA) and an increase in cAMP levels (Lee et al., 1999).

3.10. Other agents

Other signalling systems also play a key role in the regulation of APP secretion. Activation of PKA, with the subsequent generation cAMP, blocks phorbol ester-stimulated cleavage of APPs in C6 glioma cells (Efthimiopoulos and Xu). However, stimulation of the PKA pathway alone increases both the expression of the APP holoprotein and the subsequent release of APPs and A in human HEK293 cells (Lee and Marambaud). Treatment of these cells with the PKA inhibitors H89 or PKI results in a decrease in basal production of A without any effect on the generation of APPs. The apparent contradiction in these results may be due to a differential effect of cAMP in individual cell lines.

A significant number of diverse cell surface neurotransmitter receptors have also been reported to regulate APP secretion, including the G-protein- and tyrosine kinase-coupled receptors (Beyreuther; Buxbaum; Nitsch and Nitsch). Metabotropic glutamate receptor-activation of PLC, with the subsequent generation of inositol-1,4,5-triphosphate, or the activation of PLA2, also results in an increase in APPs release from neuronal cells (Nitsch and Jolly). This effect was not observed with ionotropic receptor agonists, and could be blocked by increasing cellular cAMP levels (Lee & Wurtman, 1997). Activation of the nicotinic receptor also enhances APPs secretion from PC12 cells (Kim et al., 1997). Alterations in the endogenous levels of certain neurotransmitters also influence APP expression and processing. Cholinergic lesions in the rat cortex and hippocampus result in an elevation of APP expression (Leanza, 1998). This may serve as a potential compensatory mechanism to rescue the cholinergic cells.

While changes in intracellular Ca2+ levels are pivotal in both the neuroprotective role of APP and the neurotoxic potential of A (3.3 and 4.2), alterations in Ca2+ levels also modulate the processing of APP. An increase in intracellular Ca2+ by treatment of cells with the ionophore A23187 or a caffeine-induced activation of the ryanodine receptor can result in an increase in the generation of the A peptide (Querfurth et al., 1997). Indeed, recent results have proposed that alterations in the function of the ryanodine receptor may play a critical role in the early stages of AD (Kelliher et al., 1999). These findings may be indicative of a positive feedback loop whereby an increase in A generation (with the associated amyloid deposition) raises intracellular Ca2+ levels, with a further up-regulation in A production. An increase in intracellular Ca2+ has been demonstrated to impair mitochondrial function and may influence APP processing. Treatment of COS cells with sodium azide, resulting in an inhibition of oxidative energy metabolism, increases A generation, possibly associated with an up-regulation in the actions of -secretase (Gabuzda et al., 1994). This is associated with a parallel decrease in APPs generation, an effect that was attenuated by the pretreatment of the cells with glutathione, suggesting that the effect may be mediated by free radicals (Gasparini and Gasparini).

Recent epidemiological evidence suggests that women on long-term oestrogen replacement therapy have a significantly lower incidence of AD (Stephenson and Tang). In addition to attenuating A-mediated neurotoxicity, oestrogen also acts to reduce the generation of the A peptide in HEK293 cells (Chang and Xu), with a parallel increase in the release of APPs (Jaffe et al., 1994).

The interaction of cells with elements of the extracellular matrix, as well as cell-cell adhesion, has been demonstrated to alter the expression levels of cell surface glycoprotein that modulate cell adhesion. The binding of cells to a heparan sulfate substrate increases both the expression and secretion of APP, although this effect is dependent on the level of confluency of the cells and the nature of the heparan sulfate species (Leveugle; Breen and Leveugle).

4. Amyloid function

The A peptide can exist in two primary forms: as a soluble peptide or in an aggregated state as insoluble amyloid deposits in a -pleated sheet conformation, the latter forming the basis of the senile (amyloid) plaques characteristic of AD. As A is expressed in small quantities under normal physiological conditions, numerous studies have been carried out in order to investigate the potential physiological roles of these two forms of the peptide and also to try to identify the region of the peptide that may exert these activities.

4.1. Amyloid aggregation

Initial studies on the physiological effects of A demonstrated that at low doses (10-10 M°10-8 M), the peptide exhibited neurotrophic effects, while at higher doses (> 10-7 M), the peptide was neurotoxic (Yankner et al., 1990b). As the peptide aggregates upon reaching a critical concentration (Pike et al., 1993), it has been proposed that the neurotrophic activities may be mediated by the peptide in a soluble form, while it is the aggregated form of the peptide that is neurotoxic. The soluble form of the peptide has been demonstrated to exhibit endogenous mitogenic activity (Whitson et al., 1989), in addition to acting to potentiate the effects of other mitogenic agents such as phytohemagglutinin in lymphocytes (Eckert et al., 1995), with this effect being mediated specifically by the A25°35 region of the peptide.

The majority of the available evidence suggests that the aggregated form of the A peptide is the primary neurotoxic agent both in vitro (Pike and Lorenzo) and in vivo (Giovannelli et al., 1998). However, there is recent evidence to suggest that protofibrils of A, which are metastable intermediates in amyloid fibril formation (Walsh et al., 1999), may also be toxic (Hartley et al., 1999). Upon reaching a critical concentration, A aggregates to form the insoluble amyloidogenic deposits, and there is a general age-related increase in A generation by neural cells (Turner et al., 1996). The 42 amino acid form of the peptide (A42) is considered to be the more amyloidogenic of the two forms of the peptide, and it exhibits a greater potential to generate the insoluble deposits associated with AD (Jarrett and Lansbury). Because of this, A42 is the predominant form of the peptide found in both diffuse and senile plaques in AD patients, as well as in normal ageing (Tamaoka and Fukumoto). In certain FADs, including cases of APP mutations (Suzuki and Tamaoka) or PS mutations (Scheuner et al., 1996), there is an increase in the A42:A40 ratio, with the larger form of the peptide proposed to act as a potential "seed" for amyloid deposition and plaque formation. The potential role of A42 as a "seed" for plaque formation has been strengthened by studies on plaque formation in post mortem brain samples from subjects with DS, which exhibit a pathology similar to AD. In young DS cases, the majority of plaques reacted with antibodies directed against A42, while only a subpopulation staining positive for A40. The proportion of A40-positive plaques subsequently increased dramatically with age (Iwatsubo et al., 1995). Thus, the deposition of A42 would appear to be an early event in AD-associated neurodegeneration, with this peptide acting as a seed for the subsequent deposition of the A40 peptide. The age-associated increase in the generation of A42 is further potentiated by a parallel age-related susceptibility of neurons to A toxicity (Brewer and McKee).

4.2. Calcium and amyloid toxicity

A number of mechanisms by which A may exert its toxic effects have been proposed. One of the primary events associated with A toxicity is an increase in intracellular Ca2+ levels and eventual cell death (Joseph & Han, 1992). Some studies have proposed that the insoluble A aggregates may form nonspecific ionic channels in the lipid bilayer, thus increasing the intracellular Ca2+ levels (Arispe and Rhee). These results would seem to support the proposal that the aggregation state of the peptide is a major determinant in its neurotoxicity (Pike and Pike). Other reports, however, have demonstrated that the activated channels may be both selective and voltage-dependent (Mirzabekov et al., 1994) and, therefore, have proposed a role for both L- and N-type voltage-sensitive Ca2+ channels in the modulation of A toxicity (Ueda and Price). The channel activation may be associated with the redirection of MAPK activity to phosphorylate the Ca2+ channels (Ekinci et al., 1999). The potential role of the L-type Ca2+ channels was strengthened by the evidence that channel blockers serve to attenuate A-associated apoptosis (Weiss and Copani). Furthermore, A has been reported to increase the activity of a tetraethylammonium-sensitive outward K+ current with delayed rectifier characteristics (Colom et al., 1998). As these channels have a number of electrophysiological functions, their stimulation may upset the excitability of the cell, leading to eventual cell death. Finally, A has also been demonstrated to block membrane Na+/K+-ATPase, with an associated elevation of cellular Ca2+ and neuronal injury (Mark et al., 1995). Taken together, it appears that A may act on a number of targets and the combination results in the consequent A-mediated toxicity.

Cholinergic neurons are considered to be particularly vulnerable to the actions of A, and these are among the earliest to succumb to its neurotoxic actions. The acetylcholinesterase enzyme, which has been identified as a component of the neuritic plaques, can also act as a seeding agent for A aggregation, and these complexes are more toxic than aggregates of A alone (Alvarez et al., 1998). These complexes, therefore, may serve as a potential target for certain therapeutic agents (Bonnefort et al., 1998). Furthermore, A can inhibit high-affinity choline uptake and subsequent acetylcholine release in the cortex and hippocampus, thus further exacerbating the decrease in cholinergic function associated with AD (Kar et al., 1998). At a postsynaptic level, A upsets muscarinic receptor function by disrupting the coupling of the receptor to its G-protein effector system, with this effect probably being mediated by the generation of free radicals (Kelly et al., 1996).

The key role of Ca2+ in A toxicity has been underlined by the fact that A renders neurons particularly vulnerable to the toxic effects of Ca2+ ionophores and that A toxicity is severely attenuated in cells cultured in medium with low Ca2+ levels (Mattson et al., 1992). The expression of Ca2+-binding proteins within the cell also influences its susceptibility to the neurotoxic actions of the A peptide. Cells with a high level of expression of calretinin, which are considered to have a high Ca2+-buffering capacity, exhibit a higher resistance to A toxicity (Pike & Cotman, 1995). The transfection of C6 glioma cells with calbindin-D-28k also attenuates A-induced apoptosis by stabilising intracellular Ca2+ levels (Wernyj et al., 1999).

Mitochondria play a key role in the maintenance of the cellular Ca2+ homeostasis, and decreased mitochondrial function has been associated with neuronal cell death. While A may form nonspecific Ca2+ pores in the membrane, there is also evidence that an A-associated increase in Ca2+ levels may also originate from intracellular stores (Stix and Kelliher) and thereby cause mitochondrial dysfunction (Parker and Mecocci). A deficit in mitochondrial function has also been implicated in the FAD associated with mutations in the PS protein (Mattson and Guo). This could impair the ability of the mitochondria to regulate their Ca2+ homeostasis (Kumar et al., 1994) and render the cell more susceptible to the subsequent toxic actions of A. Indeed, agents that stabilise mitochondrial function can attenuate the rate of cell death associated with PS mutations (Mattson et al., 1997b). The A peptide may also impair mitochondrial function, leading to a decreased intracellular Ca2+ homeostasis (Bozner and Pereira).

A number of biochemical events are also likely to occur, either in parallel with or downstream of the A-induced increase in intracellular Ca2+. Oxidative stress is a critical determinant in the stimulation of neuronal cell death, and A toxicity results in an increase in reactive oxygen species (ROS) and superoxide radicals, which result in oxidative damage within the cell (Thomas and Keller). The toxicity of A is attenuated by treatment with antioxidants such as vitamin E (Subramaniam et al., 1998), as well as agents that decrease intracellular superoxide levels (Paris et al., 1998). Cells with raised endogenous antioxidant enzyme levels are less susceptible to the toxic actions of A (Sagara et al., 1996). Indeed, it has been proposed that the generation of ROS may actually precede the changes in Ca2+ homeostasis (Mark et al., 1995). Oxidative damage plays a key role in AD-associated cell death, with the level of A-associated neural cell damage being correlated with the extent of lipid peroxidation within the cell (Mark et al., 1999). Furthermore, studies using a rapid autopsy protocol have demonstrated a significant reduction in the activity of the creatine kinase enzyme, which is particularly sensitive to changes in the cellular oxidative state and the presence of free radicals (Yatin et al., 1999). In addition to causing oxidative damage itself, oxidative stress can also serve to potentiate A toxicity (Pike et al., 1997), while endogenous antioxidants such as the bcl-2 proto-oncogene attenuate A toxicity (BruceKeller et al., 1998). The effects of oxidative injury, which include damage to proteins, DNA, and lipids, along with membrane lipid peroxidation, may also be partially responsible for other aspects of A-associated cell damage, including the impairment of the glucose and glutamate transport systems that occurs in neurons (Keller and Mark).

While the actual cellular mechanism by which A induces cell death remains unresolved, there is an increasing body of evidence to suggest that it occurs via an apoptotic pathway. Treatment of primary cultures of rat cortical neurons with aggregated A results in apoptotic cell death. This is accompanied by the induction of immediate early genes (c-jun, junB, c-fos, and fosB), which is characteristic of the apoptotic response (Estus et al., 1997). Furthermore, the bcl-2 proto-oncogene, which has anti-apoptotic activities, acts to suppress oxidative damage associated with A toxicity (BruceKeller et al., 1998). While there are many factors that induce apoptosis in neural cells, one is the deprivation of NGF, which itself acts via the p75NTR neurotrophin receptor. Interestingly, aggregated A may also bind to this receptor to induce apoptosis, suggesting that A may display NGF antagonistic properties (Yaar et al., 1997).

4.3. Amyloid and the cytoskeleton

A toxicity can be influenced by other cellular proteins such as the antioxidant melatonin, which inhibits fibril formation (Pappolla and Pappolla), or the plaque components thrombin and protease nexin-1 (Smithswintosky et al., 1995). Cytochalasin D, which depolymerises actin, also protects against A toxicity, although this neuroprotective effect was not observed with the microtubule-dissociating agent colchicine (Furukawa & Mattson, 1995), but rather with taxol, a microtubule-stabilising drug (Michaelis et al., 1998). These results suggest that the polymerisation state of actin may be important in controlling the cellular Ca2+ homeostasis. Cytochalasin D, which depolymerises actin filaments, has also been demonstrated to attenuate A-mediated neurotoxicity, suggesting that actin filaments may serve to mediate the Ca2+-associated neuronal cell death (Furukawa & Mattson, 1995).

4.4. Neurotransmitter modulation of amyloid toxicity

The neurotoxic effects of A may be mediated, at least in part, by modulating the actions of certain neurotransmitter systems, although the mechanism(s) underlying these interactions would appear to be quite complex. A inhibits the Na+-dependent glutamate uptake system to increase extracellular glutamate levels, in addition to a direct enhancement of glutamate-induced neurotoxicity (Harris and Morimoto). A can activate tachykinin receptors in the presence of glutamate to increase PI turnover and raise intracellular Ca2+ levels (Kimura & Schubert, 1993). However, while A enhances the action of bradykinin to increase intracellular Ca2+, this probably occurs via an inositol-1,4,5-triphosphate-independent mechanism (Huang, et al., 1998). The interaction between A and the tachykinin peptides is complex, as substance P, for example, attenuates the neurotoxic effects of A (Yankner and Kowall). Furthermore, while A modulates nicotine-stimulation of catecholamine release from adrenal chromaffin cells (Cheung et al., 1993), catecholamines themselves can exacerbate A-associated neurotoxicity by potentiating the A-associated increase in intracellular Ca2+ levels (Fu et al., 1998). While NGF also increases A-associated toxicity (Yankner et al., 1990a), A may also bind directly to the p75NTR NGF receptor to activate the NFB pathway, with a subsequent increase in ROS and free radicals (Kuner et al., 1998). The larger C100 CTF of APP, which also exhibits neurotoxic potential (Neve & Kozlowski, 1995) (Section 4.9), likewise may interact with the process of NGF-stimulated neurite outgrowth, as PC12 cells overexpressing this peptide are resistant to the neurotrophic actions of NGF (Sandhu et al., 1996). TGF- is released by microglial cells following stimulation, and plays a role in attenuating the neurodegenerative process. A, however, can bind to the TGF- receptors, where it blocks the action of the peptide, thus providing another mechanism by which A mediates its neurotoxicity (Huang, et al., 1998).

Recent epidemiological evidence suggests that hormone replacement therapy with oestrogen in postmenopausal women is associated with a decrease in the incidence and a later age of onset of AD (Stephenson and Tang). Oestrogen treatment blocks the neurotoxic effects of A by acting as a free radical scavenger (Green; Bonnefort and Pike), an effect that is potentiated by co-treatment with glutathione (Gridley et al., 1998). It can also prevent apoptosis by increasing the expression of the anti-apoptotic protein Bcl-x(L) (Pike, 1999). Other steroids may also modulate A toxicity, with corticosterone acting to increase the toxic effects of A (Goodman et al., 1996).

A has been reported to bind at low concentrations (Km, 40°80 nM) to an intracellular polypeptide termed ER A peptide-binding protein (ERAB), which is an -3-hydroxyacyl-coenzyme A dehydrogenase enzyme that is expressed at high levels in AD brain (He et al., 1998). ERAB is a type II integral membrane protein located primarily in the mitochondria (Sambamurti & Lahiri, 1998). Following A binding, there is a rapid change in the subcellular distribution of the protein, with a translocation to the plasma membrane (Yan et al., 1997). While the exact role of ERAB in A toxicity is not known, it may serve to amplify other biochemical pathways by which A mediates its effects. In particular, the binding of A to ERAB may alter the enzymatic function of the protein with the generation of the neurotoxic malondialdehyde and 4-hydroxynonenal aldehydes. This effect was not observed in cells expressing a mutant form of ERAB that binds A, but has no inherent catalytic activity. In addition, the A-ERAB interaction may render the cell vulnerable to the actions of other toxins (Yan et al., 1999).

4.5. Presenilins

While the majority of AD cases are classified as sporadic, in that there is no obvious genetic component directly responsible for the disease, ~5% of AD cases have a purely genetic basis. The genes responsible for this early-onset FAD have largely been identified. The primary components responsible for the inherited form of the disease are the two PS proteins PS1 and PS2 (Haass, 1996). These proteins, which are integral membrane proteins with 8 transmembrane domains (Li & Greenwald, 1998), are located in the ER and early Golgi apparatus (Culvenor et al., 1997), where they are proposed to play a role as chaperones in early protein processing ( Naruse et al., 1998; Section 3.4). Cells expressing the FAD mutant form of PS1 display an increased generation of A42, thus increasing the potential for A aggregation and amyloid deposits (Borchelt and Citron). A similar effect has been reported for PS2 mutations (Oyama et al., 1998). Furthermore, transgenic mice expressing the mutant forms of both APP and PS1 demonstrate an accelerated rate of plaque formation (Holcomb et al., 1998). These effects may be associated with a direct interaction between PS1 and APP (Xia et al., 1997). In addition to an increase in A generation, PS1 mutations also modify A toxicity. Transgenic mice expressing a mutant form of the PS1 protein are more susceptible to the toxic actions of the A peptide (Guo et al., 1999b), and increased oxidative stress has been proposed to play a pivotal role in this increased vulnerability (Guo et al., 1997). The potential role of free radicals in PS-stimulated A toxicity has been strengthened by an increased sensitivity of the PS1 mutant mice to other toxins, such as glutamate, which also act to increase oxidative stress (Guo et al., 1999a). A number of other potential mechanisms by which PS mutations may render cells more susceptible to A-induced toxicity include an altered Ca2+ homeostasis, mitochondrial dysfunction, an increased susceptibility to A-induced apoptosis, and an upset in key signal transduction pathways (Guo; Keller; Begley and Leissring). Cells expressing AD-associated PS1 mutations are rendered less susceptible to the toxic actions of A following overexpression of calbindin D28k, a protein with a high Ca2+-buffering capacity (Guo et al., 1998).

4.6. Apolipoprotein E

The polymorphism of the ApoE protein, which plays a role in the control of cellular cholesterol homeostasis, is one of the major risk factors for AD (Section 3.2). Those bearing either one or two copies of the ApoE4 allele have a much higher potential of developing AD, although the exact mechanism(s) underlying this are unclear. Early in vitro studies suggested that the ApoE4 allele preferentially bound the A peptide to generate amyloid fibrils (Wisniewski et al., 1994). However, more recent structural studies have proposed that ApoE4 actually binds A with a lower affinity than the other two allelic forms, thus permitting its aggregation and toxicity, while both ApoE3 and -E2 bind A with higher affinities to facilitate clearance of the peptide following its release from the cell (Jordan and Pillot). It has also been proposed, however, that the A peptide itself may influence ApoE function by altering the distribution pattern of free cholesterol within the cell, resulting in an alteration of intracellular vesicle trafficking (Liu et al., 1998). As neurons are vulnerable to changes in the lipid homeostasis, with certain neurodegenerative disease states being associated with altered membrane cholesterol levels, such a mechanism may provide another pathway through which A exerts its toxic effects.

Although ApoE3 and ApoE4 appear to bind with equal affinity to LRP, they prefer lipoprotein particles of different sizes (Dong & Weisgraber, 1996). This variation in their biochemical properties may explain the differential effects of these two ApoE isoforms on neurite outgrowth and branching in vitro, and their subsequent role in late onset AD (Nathan and Holtzman). In addition, 2-macroglobulin (Section 4.7), which is a broad-substrate specificity protease inhibitor, can also induce dimerization of LRP upon proteolytic activation, and has been shown to be a powerful modulator of the age of onset of AD (Moestrup and Blacker).

4.7. 2-Macroglobulin

The 2-macroglobulin protein (2M) is a component of the senile plaque and has been proposed by a number of research groups as a potential genetic risk factor for AD (Blacker and Liao). The actual role of 2M, however, is somewhat unclear, as other groups have been unable to confirm its role as a genetic susceptibility factor (Scott and WavrantDeVrieze). Along with ApoE, it binds to the 2M receptor/LRP. 2M attenuates amyloid fibril formation and A toxicity, possibly by maintaining A in a soluble state and preventing aggregation (Du and Hughes). A protease-activated form of 2M also degrades A and stimulates its clearance from the extracellular space, with this being inhibited by ApoE (Qiu and Zhang). This may provide a further mechanism by which the different ApoE isoforms act as genetic risk factors in AD. By forming a direct complex with A, 2M can mediate the endocytosis of the peptide via the 2M receptor/LRP pathway (Narita et al., 1997). In fact, the LRP has also been proposed as a potential genetic risk factor for AD, and this may be associated with its ability to attenuate fibril formation (Beffert et al., 1999).

4.8. The inflammatory response

The inflammatory response, characterised by the activation of microglial cells in the proximity of the lesions, is an important event in the progression of AD-associated neurodegeneration (Itagaki et al., 1989; Section 3.9). The microglial cells adhere to the amyloid fibrils via a class A scavenger receptor, and are activated by the A binding via a number of intermediate steps, including the stimulation of tyrosine kinase, G-proteins, and mitogen-activated kinase (McDonald; McDonald and Nakai). This results in the release of various neurotoxic factors that generate ROS via a NFB-mediated mechanism (Araujo and Bales), in addition to the release of other mediators of the inflammatory cascade, including tumor necrosis factor- and - (Elkhoury et al., 1996). These latter agents serve as neuroprotectants and act to decrease cellular Ca2+ levels and increase the cellular Ca2+ buffering capacity by the induction of the calbindin-D-28k protein (Mattson et al., 1995), as well as the induction of manganese superoxide dismutase, probably via an NFkB-associated pathway (Mattson and Lezoualch). A can also activate the classical C pathway by binding to the collagen-like domain of C1q (Jiang et al., 1994), and this binding promotes A aggregation (Webster et al., 1995). In addition, the A peptide can attenuate the protective actions of substance P by interacting with the serpin enzyme complex receptor (Khalil et al., 1994). The inflammatory factors also stimulate the generation of ROS. There is a complex relationship, however, between the A peptide and microglial cell activation, and while pro-inflammatory factors result in an increase in the generation of A (Bitting et al., 1996), they also act to attenuate the neurotoxic potential of the peptide (Barger et al., 1995b). Furthermore, there is a positive feedback mechanism whereby A stimulation of the microglial cells actually results in an increase in A secretion (Bitting et al., 1996), as well as potentiating the immune response by stimulating the release of inflammatory factors (Lorton, 1997). However, microglial activation may also act to attenuate the rate of A aggregation and amyloid formation, as the cells secrete a metalloprotease following activation, which is capable of degrading soluble A prior to its polymerisation (Qiu and Mentlein). The microglia are also capable of taking up and slowly degrading a limited amount of A, both as free peptide and in the aggregated state (Paresce et al., 1997). The balance between a number of variables, including protease action, the rate of A secretion, and A uptake and degradation, therefore, may determine the overall quantity of the insoluble amyloid deposits.

The aggregated A interacts with and activates the RAGE to give rise to the generation of ROS within the neuronal cells. Furthermore, A activation of the scavenger receptor on microglial cells may result in the generation of neurotoxic agents, such as excitotoxins, ROS, and nitric oxide, as well as neuroprotective agents, such as TGF- and basic fibroblast growth factor (Elkhoury; Yan and Akama). The increase in the expression levels of advanced glycation end products in AD further supports a potential role for RAGE activation in the mediation of A toxicity (Yan et al., 1994).

A large number of the studies that have been carried out to date used the A25°35 peptide, first described as the toxicologically active portion of the peptide. However, more recent studies have reported differential responses to the full-length and partial peptides, suggesting that they may employ distinct pharmacological mechanisms of action. In microglial cells, both peptides serve to increase intracellular Ca2+ levels, although the time scale of both agents is distinct. The A25°35 increases intracellular Ca2+ levels within 1 hr of the addition of the drug, while no effect was observed with the full-length A1°42 peptide until at least 6 hr after addition (Korotzer and Korotzer).

4.9. The C100 protein

There is increasing evidence that carboxyl-terminal fragments of APP may also exhibit neurotoxic activity in addition to A (Neve & Kozlowski, 1995). Initial studies demonstrated a selective neurotoxic potential of a 14°15 kDa fragment that contained intact A (Fukuchi and Fukuchi). The toxic agent was subsequently identified as a 100 amino acid CTF (termed C100; Fig. 1), which inhibits the Mg2+/Ca2+-ATPase within the ER and also the Na+/Ca2+ exchanger. This serves to compromise the ability of the cells to sequester Ca2+ within the ER, raising the levels of free intracellular Ca2+ (Kim and Kim). This effect is specific to the larger protein and is not observed with the A peptide alone. A secreted form of C100 can also coalesce to form aggregates, and it may form nonselective pores in the cell membrane, in a manner akin to A. However, C100 appears to be a more potent neurotoxin than A (Kim & Suh, 1996), and the soluble form of the protein binds with high affinity to an as yet unidentified cell surface receptor with consequent neurotoxic effects (Kozlowski et al., 1992). C100 also exhibits neurotoxic actions in vivo, and transgenic mice overexpressing the peptide demonstrate some of the neuropathological features characteristic of AD brain (Kammesheidt; Neve and OsterGranite), in addition to an impairment of both learning and LTP induction (Nalbantoglu et al., 1997). C100 is generated within the cell, where it is located primarily within the synaptosomal membrane fraction, and its production is increased in cells expressing a mutated form of APP associated with FAD (McPhie et al., 1997). This overexpression of C100 generates an age-related increase in A generation and amyloid deposition. As the generation of C100 occurs in a similar subcellular compartment to that of A, it is possible that the CTF may be generated as a potential precursor of A (Golde and Dyrks). Recent studies have also proposed that the 17 amino acid peptide APP713°730°°(numbers refer to APP770), which is partially located in the plasma membrane distal to the A peptide region, may also demonstrate neurotoxic properties (Marcon et al., 1999).

Abnormal processing of APP generates A by the - and -secretase enzymes, and therefore, the level of expression of the protein precursor influences the rate of generation of A. While the control of APP expression is multifactorial (Section 3), one of the factors modulating its expression is the A peptide itself (Busciglio et al., 1995) with a consequent decrease in APPs secretion, with the potential for a concomitant increase in A generation. This could serve as a potential A positive feedback mechanism. There is also evidence for a role for A in the generation of the neurofibrillary tangles. Treatment of a neural cell line with aggregated A results in increased tau phosphorylation (Le et al., 1995). This effect can be attenuated by decreasing APP expression using antisense oligonucleotides, suggesting that the effect may be indirectly mediated by altered cellular APP expression (Le et al., 1997). However, other studies have demonstrated that APP expression is not essential for A toxicity (Brown and White).

5. Conclusion

The processing of APP is a pivotal event in AD, and this process can be modulated by a variety of factors, including many neurotransmitter receptors, as well as the activation of diverse second messenger systems. All of these provide potential therapeutic targets for the actions of pharmacological agents that may increase the secretion of APPs and decrease the generation of the amyloidogenic A peptide. Furthermore, the identification of potentially distinct -secretase enzymes may permit the generation of specific protease inhibitors to decrease A generation. Of great interest, however, is the recent paper that describes the prevention of A deposition, and even the attenuation of the A plaque burden following immunisation with the A peptide (Schenck et al., 1999). This further underlines the importance of the A peptide as a therapeutic target. Therefore, the task of future AD research will be to identify unique mechanism(s) by which to modulate APP processing and the subsequent A deposition. While this is unlikely to reverse the neurodegeneration that has already occurred, one hopes that it will serve to slow down the rate of disease progression and prevent the occurrence of further neuronal cell loss.


The authors were supported by the Scottish Hospital Endowments Research Trust and a local trust through a Tenovus initiative (K.C.B.) and NIH Grant P01 AG11542 (C.M.C.).


Akama, K.T., Albanese, C., Pestell, R.G. and Van Eldik, L.J., 1998. Amyloid peptide stimulates nitric oxide production in astrocytes through an NFB-dependent mechanism. Proc Natl Acad Sci USA 95, pp. 5795°5800. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Akar, C.A. and Wallace, W.C., 1998. Amyloid precursor protein modulates the interaction of nerve growth factor with p75 receptor and potentiates its activation of trkA phosphorylation. Mol Brain Res 56, pp. 125°132. SummaryPlus | Article | Journal Format-PDF (246 K)

Akiyama, H., Ikeda, K., Katoh, M., McGeer, E.G. and McGeer, P.L., 1994. Expression of MRP14, 27E10, interferon-alpha and leukocyte common antigen by reactive microglia in postmortem human brain tissue. J Neuroimmunol 50, pp. 195°201. Abstract |  $Order Document

Alvarez, A., Alarcon, R., Opazo, C., Campos, E.O., Munoz, F.J., Calderon, F.H., Dajas, F., Gentry, M.K., Doctor, B.P., DeMello, F.G. and Inestrosa, N.C., 1998. Stable complexes involving acetylcholinesterase and amyloid-beta peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer's fibrils. J Neurosci 18, pp. 3213°3223. Abstract |  $Order Document

Anderson, J.P., Chen, Y., Kim, K.S. and Robakis, N.K., 1992. An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a potentially amyloidogenic sequence. J Neurochem 59, pp. 2328°2331 a. BIOSIS Previews | EMBASE |  $Order Document

Anderson, R.G.W., 1993. Caveolae°°where incoming and outgoing messengers meet. Proc Natl Acad Sci USA 90, pp. 10909°10913. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Anderson, R.G.W., Kamen, B.A., Rothberg, K.G. and Lacey, S.W., 1992. Potocytosis°°sequestration and transport of small molecules by caveolae. Science 255, pp. 410°411 b. EMBASE |  $Order Document

Ando, K., Oishi, M., Takeda, S., Iijima, K., Isohara, T., Nairn, A.C., Kirino, Y., Greengard, P. and Suzuki, T., 1999. Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation. J Neurosci 19, pp. 4421°4427. Abstract |  $Order Document

Arami, S., Jucker, M., Schachner, M. and Welzl, H., 1996. The effect of continuous intraventricular infusion of L1 and NCAM antibodies on spatial learning in rats. Behav Brain Res 81, pp. 81°87. Abstract | Journal Format-PDF (793 K)

Araujo, D.M. and Cotman, C.W., 1992. Beta-amyloid stimulates glial cells in vitro to produce growth factors that accumulate in senile plaques in Alzheimer's disease. Brain Res 569, pp. 141°145. EMBASE |  $Order Document

Arispe, N., Pollard, H.B. and Rojas, E., 1993. Giant multilevel cation channels formed by Alzheimer's disease amyloid protein [A(1°40)] in bilayer membranes. Proc Natl Acad Sci USA 90, pp. 10573°10577. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Bales, K.R., Du, Y.S., Dodel, R.C., Yan, G.M., HamiltonByrd, E. and Paul, S.M., 1998. The NF-kappa B/Rel family of proteins mediates A beta-induced neurotoxicity and glial activation. Mol Brain Res 57, pp. 63°72. SummaryPlus | Article | Journal Format-PDF (507 K)

Barger, S.W. and Van Eldik, L.J., 1992. S100 stimulates calcium fluxes in glial and neuronal cells. J Biol Chem 267, pp. 9689°9694. EMBASE | BIOTECHNOBASE |  $Order Document

Barger, S.W., Fiscus, R.R., Ruth, P., Hofmann, F. and Mattson, M.P., 1995. Role of cyclic-GMP in the regulation of neuronal calcium and survival by secreted forms of -amyloid precursor. J Neurochem 64, pp. 2087°2096 a. Abstract |  $Order Document

Barger, S.W., Horster, D., Furukawa, K., Goodman, Y., Krieglstein, J. and Mattson, M.P., 1995. Tumor necrosis factor-alpha and tumor necrosis factor- protect neurons against amyloid -peptide toxicity°°evidence for involvement of a -B binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 92, pp. 9328°9332 b. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Baskin, F., Rosenberg, R.N. and Greenberg, B.D., 1991. Increased release of an amyloidogenic C-terminal Alzheimer amyloid precursor protein fragment from stressed PC12 cells. J Neurosci Res 29, pp. 127°132. EMBASE |  $Order Document

Beffert, U., Aumont, N., Dea, D., LussierCacan, S., Davignon, J. and Poirier, J., 1998. -Amyloid peptides increase the binding and internalization of apolipoprotein E to hippocampal neurons. J Neurochem 70, pp. 1458°1466. Abstract |  $Order Document

Beffert, U., Arguin, C. and Poirier, J., 1999. The polymorphism in exon 3 of the low density lipoprotein receptor-related protein gene is weakly associated with Alzheimer's disease. Neurosci Lett 259, pp. 29°32. SummaryPlus | Article | Journal Format-PDF (66 K)

Begley, J.G., Duan, W., Chan, S., Duff, K. and Mattson, M.P., 1999. Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J Neurochem 72, pp. 1030°1039. Abstract |  $Order Document

Beher, D., Hesse, L., Masters, C.L. and Multhaup, G., 1996. Regulation of amyloid protein precursor (APP) binding to collagen and mapping of the binding sites on APP and collagen type I. J Biol Chem 271, pp. 1613°1620. Abstract |  $Order Document

Benussi, L., Govoni, S., Gasparni, L., Bretti, G., Trabuchi, M., Bianchetti, A. and Racchi, M., 1998. Specific role for protein kinase C in the constitutive and regulated secretion of amyloid precursor protein in human skin fibroblasts. Neurosci Lett 240, pp. 97°101. SummaryPlus | Article | Journal Format-PDF (125 K)

Bergamaschi, S., Binetti, G., Govoni, S., Wetsel, W.C., Battaini, F., Trabucchi, M., Bianchetti, A. and Racchi, M., 1995. Defective phorbol ester-stimulated secretion of beta-amyloid precursor protein from Alzheimer's disease fibroblasts. Neurosci Lett 201, pp. 1°4. Abstract | Journal Format-PDF (359 K)

BergerSweeney, J., McPhie, D.L., Arters, J.A., Greenan, J., OsterGranite, M.L. and Neve, R.L., 1999. Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Mol Brain Res 66, pp. 150°162. SummaryPlus | Article | Journal Format-PDF (1239 K)

Beyreuther, K., Multhaup, G., Monning, U., Sandbrink, R., Beher, D., Hesse, L., Snall, D.H. and Masters, C.L., 1996. Regulation of APP expression, biogenesis and metabolism by extracellular matrix and cytokines. Ann N Y Acad Sci 777, pp. 74°75.

Bitting, L., Naidu, A., Cordell, B. and Murphy, G.M., 1996. -Amyloid peptide secretion by a microglial cell line is induced by -amyloid (25°35) and lipopolysaccharide. J Biol Chem 271, pp. 16084°16089. Abstract |  $Order Document

Blacker, D., Wilcox, M.A., Laird, N.M., Rodes, L., Horvath, S.M., Go, R.C.P., Perry, R., Watson, B., Bassett, S.S., McInnis, M.G., Albert, M.S., Hyman, B.T. and Tanzi, R.E., 1998. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nat Genet 19, pp. 357°360. Abstract |  $Order Document

Bodovitz, S. and Klein, W.L., 1996. Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 271, pp. 4436°4440. Abstract |  $Order Document

Bonnefort, A.B., Munoz, F.J. and Inestrosa, N.C., 1998. Estrogen protects neuronal cells from the cytotoxicity induced by acetylcholinesterase-amyloid complexes. FEBS Lett 441, pp. 220°224.

Borchelt, D.R., Thinakaran, G., Eckman, C.B., Lee, M.K., Davenport, F., Ratovitsky, T., Prada, C.M., Kim, G., Seekins, S., Yager, D., Slunt, H.H., Wang, R., Seeger, M., Levey, A.I., Gandy, S.E., Copeland, N.G., Jenkins, N.A., Price, D.L., Younkin, S.G. and Sisodia, S.S., 1996. Familial Alzheimer's disease-linked presenilin I variants elevate A1°42/1°40 ratio in vitro and in vivo. Neuron 17, pp. 1005°1013. EMBASE |  $Order Document

Borg, J.P., Ooi, J., Levy, E. and Margolis, B., 1996. The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol Cell Biol 16, pp. 6229°6241. Abstract |  $Order Document

Borg, J.P., Yang, Y.N., DeTaddeoBorg, M., Margolis, B. and Turner, R.S., 1998. The X11 alpha protein slows cellular amyloid precursor protein processing and reduces A beta 40 and A beta 42 secretion. J Biol Chem 273, pp. 14761°14766. Abstract |  $Order Document

Bouchard, R.W. and Rossor, M.N., 1996. Typical clinical features. In: Gauthier, S. Editor, , 1996. Clinical Diagnosis and Management of Alzheimer's Disease Martin Dunitx Ltd, London, pp. 35°50.

Bouillot, C., Prochaintz, A., Rougon, G. and Allinquant, B., 1996. Axonal amyloid precursor protein expressed by neurons in vitro is present in a membrane fraction with caveolae-like properties. J Biol Chem 271, pp. 7640°7644. Abstract |  $Order Document

Bozner, P., Grishko, V., LeDoux, S.P., Wilson, G.L., Chyan, Y.C. and Pappolla, M.A., 1997. The amyloid beta protein induces oxidative damage of mitochondrial DNA. J Neuropathol Exp Neurol 56, pp. 1356°1362. Abstract |  $Order Document

Breen, K.C., 1992. APP-collagen interaction is mediated by a heparin bridge mechanism. Mol Chem Neuropathol 16, pp. 109°121. EMBASE |  $Order Document

Breen, K.C., 1995. Heparin induction of -amyloid precursor protein in a neural cell line is regulated by cell confluency state. Amyloid: Int J Exp Clin Invest 2, pp. 17°21. Elsevier BIOBASE |  $Order Document

Breen, K.C., Bruce, M.T. and Anderton, B.H., 1991. The beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion. J Neurosci Res 28, pp. 90°100. EMBASE |  $Order Document

Breen, K.C., Coughlan, C.M. and Hayes, F.D., 1998. The role of glycoproteins in neural development, function and disease. Mol Neurobiol 16, pp. 163°220. BIOSIS Previews | EMBASE |  $Order Document

Brewer, G.J., 1998. Age-related toxicity to lactate, glutamate, and beta-amyloid in cultured adult neurons. Neurobiol Aging 19, pp. 561°568. SummaryPlus | Article | Journal Format-PDF (223 K)

Brouillet, E., Trembleau, A., Galanaud, D., Volovitch, M., Bouillot, C., Valenza, C., Prochiantz, A. and Allinquant, B., 1999. The amyloid precursor protein interacts with Go heterotrimeric protein within a cell compartment specialized in signal transduction. J Neurosci 19, pp. 1717°1727. Abstract |  $Order Document

Brown, D.R., 1998. Toxicity of a -amyloid peptide fragment to neurones with reduced APP expression. Alzheimer Rep 1, pp. 223°231.

BruceKeller, A.J., Begley, J.G., Fu, W.M., Butterfield, D.A., Bredesen, D.E., Hutchins, J.B., Hensley, K. and Mattson, M.P., 1998. Bcl-2 protects isolated plasma and mitochondrial membranes against lipid peroxidation induced by hydrogen peroxide and amyloid beta-peptide. J Neurochem 70, pp. 31°39. Abstract |  $Order Document

Brugg, B., Dubreuil, Y.L., Huber, G., Wollman, E.E., Delhayebouchaud, N. and Mariani, J., 1995. Inflammatory processes induce -amyloid precursor protein changes in mouse brain. Proc Natl Acad Sci USA 92, pp. 3032°3035. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Budd, S.L. and Nicholls, D.G., 1996. Mitochondrial calcium regulation and acute glutamate toxicity in cultured cerebellar granule cells. J Neurochem 67, pp. 2282°2291. Abstract |  $Order Document

Busciglio, J., Gabuzda, D.H., Matsudaira, P. and Yankner, B.A., 1993. Generation of -amyloid in the secretory pathway in neuronal and non-neuronal cells. Proc Natl Acad Sci USA 90, pp. 2092°2096. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Busciglio, J., Lorenzo, A., Yeh, J. and Yankner, B.A., 1995. Amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14, pp. 879°888. Abstract |  $Order Document

Buxbaum, J.D. and Greengard, P., 1996. Regulation of APP processing by intra- and intercellular signals. Ann N Y Acad Sci 777, pp. 327°331. BIOSIS Previews | EMBASE |  $Order Document

Buxbaum, J.D., Gandy, S.E., Cicchetti, P., Ehrlich, M.E., Czernik, A.J., Fracasso, R.P., Ramabhadran, T.V., Unterbeck, A.J. and Greengard, P., 1990. Processing of Alzheimer /A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proc Natl Acad Sci USA 87, pp. 6003°6006. EMBASE | BIOTECHNOBASE |  $Order Document

Buxbaum, J.D., Oishi, M., Chen, H.I., Pinkaskramarski, R., Jaffe, E.A., Gandy, S.E. and Greengard, P., 1992. Cholinergic agonists and interleukin-1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein-precursor. Proc Natl Acad Sci USA 89, pp. 10075°10078. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Buxbaum, J.D., Thinakaran, G., Koliatsos, V., O'Callahan, J., Slunt, H.H., Price, D.L. and Sisodia, S.S., 1998. Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path. J Neurosci 18, pp. 9629°9637. Abstract |  $Order Document

Caceres, J. and Brandan, E., 1997. Interaction between Alzheimer's disease beta A4 precursor protein (APP) and the extracellular matrix: evidence for the participation of heparan sulfate proteoglycans. J Cell Biochem 65, pp. 145°158. Abstract |  $Order Document | CrossRef

Caporaso, G.L., Gandy, S.E., Buxbaum, J.D. and Greengard, P., 1992. Chloroquine inhibits intracellular degradation but not secretion of Alzheimer /A4 amyloid precursor protein. Proc Natl Acad Sci USA 89, pp. 2252°2256. EMBASE | BIOTECHNOBASE |  $Order Document

Caputi, A., Barindelli, S., Pastorino, L., Cimino, M., Buxbaum, J.D., Cattabeni, F. and Di Luca, M., 1997. Increased secretion of the amino terminal fragment of amyloid precursor protein in brains of rats with a constitutive up-regulation of protein kinase C. J Neurochem 68, pp. 2523°2529. BIOSIS Previews | EMBASE |  $Order Document

Castillo, G.M., Ngo, C., Cummings, J., Wight, T.N. and Snow, A.D., 1997. Perlecan binds to the beta-amyloid proteins (A beta) of Alzheimer's disease, accelerates A beta fibril formation, and maintains A beta fibril stability. J Neurochem 69, pp. 2452°2465. Abstract |  $Order Document

Chang, D., Kwan, J. and Timiras, P.S., 1997. Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line. Adv Exp Med Biol 429, pp. 261°271. EMBASE |  $Order Document

Chang, W.J., Rothberg, K.G., Kamen, B.A. and Anderson, R.G.W., 1992. Lowering the cholesterol content of MA104 cells inhibits receptor-mediated transport of folate. J Cell Biol 118, pp. 63°69. EMBASE |  $Order Document

Chapman, P.F., White, G.I., Jones, M.W., Cooper-Blacketer, D., Marshall, V.J., Irizarry, M., Younkin, L., Good, M.A., Bliss, T.V.P., Hyman, B.T., Younkin, S.G. and Hsiao, K.K., 1999. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2, pp. 271°276. BIOSIS Previews |  $Order Document

Chen, M. and Yankner, B.A., 1991. An antibody to amyloid and the amyloid precursor protein inhibits cell-substratum adhesion in many mammalian cell types. Neurosci Lett 125, pp. 223°226. EMBASE |  $Order Document

Cheung, N.S., Small, D.H. and Livett, B.G., 1993. An amyloid peptide, A4 25°35, mimics the function of substance P on modulation of nicotine-evoked secretion and desensitisation in cultured bovine adrenal chromaffin cells. J Neurochem 60, pp. 1163°1166. BIOSIS Previews |  $Order Document

Chow, N.W., Korenberg, J.R., Chen, X.N. and Neve, R.L., 1996. APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein. J Biol Chem 271, pp. 11339°11346. Abstract |  $Order Document

Citron, M., Diehl, T.S., Gordon, G., Biere, A.L., Seubert, P. and Selkoe, D.J., 1996. Evidence that the 42- and 40-amino acid formed of the amyloid protein are generated from the amyloid precursor protein by different protease activities. Proc Natl Acad Sci USA 93, pp. 13170°13175. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., JohnsonWood, K., Lee, M., Seubert, P., Davis, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I., Rommens, J., Kim, S., Schenk, D., Fraser, P., Hyslop, P.S.G. and Selkoe, D.J., 1997. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3, pp. 67°72. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Clarris, H.J., Nurcombe, V., Small, D.H., Beyreuther, K. and Masters, C.L., 1994. Secretion of nerve growth factor from septum stimulates neurite outgrowth and release of the amyloid precursor protein of Alzheimer's disease from hippocampal explants. J Neurosci Res 38, pp. 248°258. BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document

Clarris, H.J., Cappai, R., Heffernan, D., Beyreuther, K., Masters, C.L. and Small, D.H., 1997. Identification of heparin-binding domains in the amyloid precursor protein of Alzheimer's disease by deletion mutagenesis and peptide mapping. J Neurochem 68, pp. 1164°1172. Abstract |  $Order Document

Cobb, M.H. and Goldsmith, E.J., 1995. How MAP kinases are regulated. J Biol Chem 270, pp. 14843°14846. Abstract |  $Order Document

Cole, G.M., Huynh, T.V. and Saitoh, T., 1989. Evidence for lysosomal processing of amyloid -protein precursor in cultured cells. Neurochem Res 14, pp. 933°939. EMBASE |  $Order Document

Colom, L.V., Diaz, M.E., Beers, D.R., Neely, A., Xie, W.J. and Appel, S.H., 1998. Role of potassium channels in amyloid-induced cell death. J Neurochem 70, pp. 1925°1934. Abstract |  $Order Document

Conlon, R.A., Reaume, A.G. and Rossant, J., 1995. Notch 1 is required for the coordinate segmentation of somites. Development 121, pp. 1533°1545. Abstract |  $Order Document

Conrad, P.A., Smart, E.J., Ying, Y.S., Anderson, R.G.W. and Bloom, G.S., 1995. Caveolin cycles between plasma membrane caveolae and the Golgi complex by microtubule-dependent and microtubule-independent steps. J Cell Biol 131, pp. 1421°1433. Abstract |  $Order Document

Cook, D.G., Forman, M.S., Sung, J.C., Leight, S., Kolson, D.L., Iwatsubo, T., Lee, V.M.Y. and Doms, R.W., 1997. Alzheimer's A beta(1°42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med 3, pp. 1021°1023. BIOSIS Previews | EMBASE |  $Order Document

Copani, A., Bruno, V., Battaglia, G., Leanza, G., Pellitteri, R., Russo, A., Stanzani, S. and Nicoletti, F., 1995. Activation of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by -amyloid peptide. Mol Pharmacol 47, pp. 890°897. Abstract |  $Order Document

Cotman, C.W., Pike, C.J. and Copani, A., 1992. -Amyloid neurotoxicity: a discussion of in vitro findings. Neurobiol Aging 13, p. 587. BIOSIS Previews | EMBASE |  $Order Document

Couet, J., Li, S.W., Okamoto, T., Ikezu, T. and Lisanti, M.P., 1997. Identification of peptide and protein ligands for the caveolin-scaffolding domain°°implications for the interaction of caveolin with caveolae-associated proteins. J Biol Chem 272, pp. 6525°6533. Abstract |  $Order Document

Coulson, E.J., Barrett, G.L., Storey, E., Bartlett, P.F., Beyreuther, K. and Masters, C.L., 1997. Down-regulation of the amyloid protein precursor of Alzheimer's disease by antisense oligonucleotides reduces neuronal adhesion to specific substrata. Brain Res 770, pp. 72°80. SummaryPlus | Article | Journal Format-PDF (287 K)

Cullen, W.K., Wu, J.Q., Anwyl, R. and Rowan, M.J., 1996. Beta-amyloid produces a delayed NMDA receptor-dependent reduction in synaptic transmission in rat hippocampus. Neuroreport 8, pp. 87°92.

Cullen, W., Suh, Y.-H., Anwyl, R. and Rowan, M.J., 1997. Block of LTP in rat hippocampus in vivo by amyloid precursor protein fragments. Neuroreport 8, pp. 3213°3217. Abstract |  $Order Document

Culvenor, J.G., Maher, F., Evin, G., MalchiodiAlbedi, F., Cappai, R., Underwood, J.R., Davis, J.B., Karran, E.H., Roberts, G.W., Beyreuther, K. and Masters, C.L., 1997. Alzheimer's disease-associated presenilin 1 in neuronal cells: evidence for localization to the endoplasmic reticulum Golgi intermediate compartment. J Neurosci Res 49, pp. 719°731. BIOSIS Previews | EMBASE |  $Order Document | CrossRef

Davis-Salinas, J., Saporitoirwin, S.M., Donovan, F.M., Cunningham, D.D. and Vannostrand, W.E., 1994. Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid -protein precursor. J Biol Chem 269, pp. 22623°22627. Abstract |  $Order Document

Dawson, G.R., Seabrook, G.R., Zheng, H., Smith, D.W., Graham, S., O'Dowd, G., Bowery, B.J., Boyce, S., Trumbauer, M.E., Chen, H.Y., Van der Ploeg, L.H.T. and Sirinathsinghji, D.J.S., 1999. Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the amyloid precursor protein. Neuroscience 90, pp. 1°13. Abstract | Journal Format-PDF (1050 K)

Dawson, V.L., Dawson, T.M. and Wamsley, J.K., 1990. Muscarinic and dopaminergic receptor subtypes on striatal cholinergic interneurons. Brain Res Bull 25, pp. 903°912. EMBASE |  $Order Document

Dehouck, B., Fenart, L., Dehouck, M.P., Pierce, A., Torpier, G. and Cecchelli, R., 1997. A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier. J Cell Biol 138, pp. 877°889. Abstract |  $Order Document

Delbo, R., Angeretti, N., Lucca, E., Desimoni, M.G. and Forloni, G., 1995. Reciprocal control of inflammatory cytokines, Il-1 and Il-6, and -amyloid production in cultures. Neurosci Lett 188, pp. 70°74. Abstract | Journal Format-PDF (483 K)

DesdouitsMagnen, J., Desdouits, F., Takeda, S., Syu, L.J., Saltiel, A.R., Buxbaum, J.D., Czernik, A.J., Nairn, A.C. and Greengard, P., 1998. Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade. J Neurochem 70, pp. 524°530. Abstract |  $Order Document

Destrooper, B., Umans, L., Vanleuven, F. and Vandenberghe, H., 1993. Study of the synthesis and secretion of normal and artificial mutants of murine amyloid precursor protein (APP)°°cleavage of APP occurs in a late compartment of the default secretion pathway. J Cell Biol 121, pp. 295°304.

DeStrooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., VonFigura, K. and VanLeuven, F., 1998. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, pp. 387°390.

DeStrooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J.S., Schrooter, E.H., Schrijvers, V., Wolfe, M.S., Ray, W.J., Goate, A. and Kpoan, R., 1999. A presenilin-1-dependent -secretase-like protease mediates release of Notch intracellular domain. Nature 398, pp. 518°522. Elsevier BIOBASE | EMBASE |  $Order Document

deWeerd, W.F.C. and LeebLundberg, L.M.F., 1997. Bradykinin sequesters B2 bradykinin receptors and the receptor-coupled G alpha subunits G alpha(q) and G alpha(i) in caveolae in DDT1 MF-2 smooth muscle cells. J Biol Chem 272, pp. 17858°17866. BIOTECHNOBASE |  $Order Document

Dewji, N.N. and Singer, S.J., 1997. Cell surface expression of the Alzheimer's disease-related presenilin proteins. Proc Natl Acad Sci USA 94, pp. 9026°9031.

Dewji, N.N. and Singer, S.J., 1998. Specific intercellular binding of the beta-amyloid precursor protein to the presenilins induces intercellular signaling: its significance for Alzheimer's disease. Proc Natl Acad Sci USA 95, pp. 15055°15060. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Dickson, D.W., 1997. The pathogenesis of senile plaques. J Neuropathol Exp Neurol 56, pp. 321°339. Abstract |  $Order Document

Doherty, P., Rowett, L.H., Moore, S.E., Mann, D.A. and Walsh, F.S., 1991. Neurite outgrowth in response to transfected N-CAM and N-cadherin reveals fundamental differences in neuronal responsiveness to CAMs. Neuron 6, pp. 247°258. EMBASE | BIOTECHNOBASE |  $Order Document

Dong, L.M. and Weisgraber, K.H., 1996. Human apolipoprotein E4 domain interaction°°arginine 61 and glutamic acid 255 interact to direct the preference for very low density lipoproteins. J Biol Chem 271, pp. 19053°19057. Abstract |  $Order Document

Doyle, E., Bruce, M.T., Breen, K.C., Smith, D.C., Anderton, B.H. and Regan, C.M., 1990. Intraventricular infusions of antibodies to amyloid--protein precursor impair the acquisition of a passive avoidance response in the rat. Neurosci Lett 115, pp. 97°102. EMBASE |  $Order Document

Doyle, E., Nolan, P.M., Bell, R. and Regan, C.M., 1992. Intraventricular infusions of antineural cell-adhesion molecules in a discrete post-training period impair consolidation of a passive avoidance response in the rat. J Neurochem 59, pp. 1570°1573. BIOSIS Previews | EMBASE |  $Order Document

Du, Y.S., Bales, K.R., Dodel, R.C., Liu, X.D., Glinn, M.A., Horn, J.W., Little, S.P. and Paul, S.M., 1998. Alpha(2)-macroglobulin attenuates beta-amyloid peptide 1°40 fibril formation and associated neurotoxicity of cultured fetal rat cortical neurons. J Neurochem 70, pp. 1182°1188. Abstract |  $Order Document

Duilio, A., Zambrano, N., Mogavero, A.R., Ammendola, R., Cimino, F. and Russo, T., 1991. A rat brain messenger-RNA encoding a transcriptional activator homologous to the DNA-binding domain of retroviral integrases. Nucleic Acids Res 19, pp. 5269°5274. EMBASE | BIOTECHNOBASE |  $Order Document

Dyrks, T., Dyrks, E., Monning, U., Urmoneit, B., Turner, J. and Beyreuther, K., 1993. Generation of -A4 from the amyloid protein precursor and fragments thereof. FEBS Lett 335, pp. 89°93. Abstract |  $Order Document

Eckert, A., Forstl, H., Hartmann, H., Czech, C., Monning, U., Beyreuther, K. and Muller, W.E., 1995. The amplifying effect of -amyloid on cellular calcium signaling is reduced in Alzheimer's disease. Neuroreport 6, pp. 1199°1202. Abstract |  $Order Document

Efthimiopoulos, S., Felsenstein, K.M., Sambamurti, K., Robakis, N.K. and Refolo, L.M., 1994. Study of the phorbol ester effect on Alzheimer's amyloid precursor protein processing: sequence requirements and involvement of a cholera toxin sensitive protein. J Neurosci Res 38, pp. 81°91.

Efthimiopoulos, S., Punj, S., Manolopoulos, V., Pangalos, M., Wang, G.P., Refolo, L.M. and Robakis, N.K., 1996. Intracellular cyclic-AMP inhibits constitutive and phorbol ester-stimulated secretory cleavage of amyloid precursor protein. J Neurochem 67, pp. 872°875. Abstract |  $Order Document

Efthimiopoulos, S., Floor, E., Georgakopoulos, A., Shioi, J., Cui, W., Yasothornsrikul, S., Hook, V.Y.H., Wisniewski, T., Buee, L. and Robakis, N.K., 1998. Enrichment of presenilin 1 peptides in neuronal large dense-core and somatodendritic clathrin-coated vesicles. J Neurochem 71, pp. 2365°2372. Abstract |  $Order Document

Ekinci, F.J., Malik, K.U. and Shea, T.B., 1999. Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to amyloid. J Biol Chem 274, pp. 30322°30327. Abstract |  $Order Document

Elkhoury, J., Hickman, S.E., Thomas, C.A., Cao, L., Silverstein, S.C. and Loike, J.D., 1996. Scavenger receptor-mediated adhesion of microglia to amyloid fibrils. Nature 382, pp. 716°719. Elsevier BIOBASE |  $Order Document

Emmerling, M.R., Moore, C.J., Doyle, P.D., Carroll, R.T. and Davis, R.E., 1993. Phospholipase-A2 activation influences the processing and secretion of the amyloid precursor protein. Biochem Biophys Res Commun 197, pp. 292°297. Abstract |  $Order Document | CrossRef

Estus, S., Golde, T.E., Kunishita, T., Blades, D., Lowery, D., Eisen, M., Usiak, M., Qu, X., Tabira, T., Greenberg, B.D. and Younkin, S.G., 1992. Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255, pp. 726°728. EMBASE |  $Order Document

Estus, S., Tucker, H.M., vanRooyen, C., Wright, S., Brigham, E.F., Wogulis, M. and Rydel, R.E., 1997. Aggregated amyloid-beta protein induces cortical neuronal apoptosis and concomitant "apoptotic" pattern of gene induction. J Neurosci 17, pp. 7736°7745. Abstract |  $Order Document

Fazeli, M.S., Breen, K.C., Errington, M.L. and Bliss, T.V.P., 1994. Increase in extracellular NCAM and amyloid precursor protein following induction of long-term potentiation in the dentate gyrus of anaesthetized rats. Neurosci Lett 169, pp. 77°80. Abstract |  $Order Document

Feron, O., Smith, T.W., Michel, T. and Kelly, R.A., 1997. Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J Biol Chem 272, pp. 17744°17748. Abstract |  $Order Document

Ferraridileo, G., Mash, D.C. and Flynn, D.D., 1995. Attenuation of muscarinic receptor-G-protein interaction in Alzheimer's disease. Mol Chem Neuropathol 24, pp. 69°91. Abstract |  $Order Document

FigueiredoPereira, M.E., Efthimiopoulos, S., Tezapsidis, N., Buku, A., Ghiso, J., Mehta, P. and Robakis, N.K., 1999. Distinct secretases, a cysteine protease and a serine protease, generate the C termini of amyloid beta-proteins A beta(1°40) and A beta(1°42), respectively. J Neurochem 72, pp. 1417°1422. Abstract |  $Order Document

Fiore, F., Zambrano, N., Minopoli, G., Donini, V., Duilio, A. and Russo, T., 1995. The regions of the Fe65 protein homologous to the phosphotyrosine interaction phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer's amyloid precursor protein. J Biol Chem 270, pp. 30853°30856. Abstract |  $Order Document

Flanders, K.C., Lippa, C.F., Smith, T.W., Pollen, D.A. and Sporn, M.B., 1995. Altered expression of transforming growth factor- in Alzheimer's disease. Neurology 45, pp. 1561°1569. Abstract |  $Order Document

Fossgreen, A., Bruckner, B., Czech, C., Masters, C.L., Beyreuther, K. and Paro, R., 1998. Transgenic Drosophila expressing human amyloid precursor protein show gamma-secretase activity and a blistered-wing phenotype. Proc Natl Acad Sci USA 95, pp. 13703°13708. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Fu, W.M., Luo, H., Parthasarathy, S. and Mattson, M.P., 1998. Catecholamines potentiate amyloid beta-peptide neurotoxicity: involvement of oxidative stress, mitochondrial dysfunction, and perturbed calcium homeostasis. Neurobiol Dis 5, pp. 229°243. EMBASE |  $Order Document | CrossRef

Fukuchi, K.I., Kamino, K., Deeb, S.S., Furlong, C.E., Sundstrom, J.A., Smith, A.C. and Martin, G.M., 1992. Expression of a carboxy-terminal region of the amyloid precursor protein in a heterologous culture of neuroblastoma cells: evidence for altered processing and selective neurotoxicity. Mol Brain Res 16, pp. 37°46. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Fukuchi, K., Sopher, B., Furlong, C.E., Smith, A.C., Dang, N. and Martin, G.M., 1993. Selective neurotoxicity of COOH-terminal fragments of the amyloid precursor protein. Neurosci Lett 154, pp. 145°148. BIOSIS Previews | EMBASE |  $Order Document

Fukumoto, H., AsamiOdaka, A., Suzuki, N., Shimada, H., Ihara, Y. and Iwatsubo, T., 1996. Amyloid beta protein deposition in normal aging has the same characteristics as that in Alzheimer's disease°°predominance of A beta 42(43) and association of A beta 40 with cored plaques. Am J Pathol 148, pp. 259°265. Abstract |  $Order Document

Fukuyama, R., Chandrasekaran, K. and Rapoport, S.I., 1993. Nerve growth factor-induced neuronal differentiation is accompanied by differential induction and localization of the amyloid precursor protein (APP) in PC12 cells and variant PC12s cells. Mol Brain Res 17, pp. 17°22. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Furukawa, K. and Mattson, M.P., 1995. Cytochalasins protect hippocampal neurons against amyloid peptide toxicity°°evidence that actin depolymerization suppresses Ca2+ influx. J Neurochem 65, pp. 1061°1068. Abstract |  $Order Document

Furukawa, K. and Mattson, M.P., 1998. Secreted amyloid precursor protein selectively suppresses N-methyl--asparte currents in hippocampal neurons: involvement of cyclic GMP. Neuroscience 83, pp. 429°438. BIOSIS Previews | EMBASE |  $Order Document

Furukawa, K., Barger, S.W., Blalock, E.M. and Mattson, M.P., 1996. Activation of K+ channels and suppression of neuronal activity by secreted amyloid precursor protein. Nature 379, pp. 74°78 a. BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document

Furukawa, K., Sopher, B.L., Rydel, R.E., Begley, J.G., Pham, D.G., Martin, G.M., Fox, M. and Mattson, M.P., 1996. Increased activity-regulating and neuroprotective efficacy of -secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin binding domain. J Neurochem 67, pp. 1882°1896 b. Abstract |  $Order Document

Gabuzda, D., Busciglio, J., Lan Bo, C., Matsudaira, P. and Yankner, B.A., 1994. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 269, pp. 13623°13628. Abstract |  $Order Document

Gasparini, L., Racchi, M., Benussi, L., Curti, D., Binetti, G., Bianchetti, A., Trabucchi, M. and Govoni, S., 1997. Effect of energy shortage and oxidative stress on amyloid precursor protein metabolism in COS cells. Neurosci Lett 231, pp. 113°117. SummaryPlus | Article | Journal Format-PDF (219 K)

Gasparini, L., Benussi, L., Bianchetti, A., Binetti, G., Curti, D., Govoni, S., Moraschi, S., Racchi, M. and Trabucchi, M., 1999. Energy metabolism inhibition impairs amyloid precursor protein secretion from Alzheimer's fibroblasts. Neurosci Lett 263, pp. 197°200. SummaryPlus | Article | Journal Format-PDF (232 K)

Gervais, F.G., Xu, D.G., Robertson, G.S., Vaillancourt, J.P., Zhu, Y.X., Huang, J.Q., LeBlanc, A., Smith, D., Rigby, M., Shearman, M.S., Clarke, F.E., Zheng, H., VanDerPloeg, L.H.T., Ruffolo, S.C., Thornberry, N.A., Xanthoudakis, S., Zamboni, R.J., Roy, S. and Nicholson, D.W., 1999. Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 97, pp. 395°406. Abstract |  $Order Document

Ghiso, J., Rostagno, A., Gardella, J.E., Liem, L., Gorevic, P.D. and Frangione, B., 1992. A 109-amino acid C-terminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell-adhesion. Biochem J 288, pp. 1053°1059. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Giambarella, U., Murayama, Y., Ikezu, T., Fujita, T. and Nishimoto, I., 1997. Potential CRE suppression by familial Alzheimer's mutants of APP independent of adenylyl cyclase regulation. FEBS Lett 412, pp. 97°101 a. SummaryPlus | Article | Journal Format-PDF (1349 K)

Giambarella, U., Yamatsuji, T., Okamoto, T., Matsui, T., Ikezu, T., Murayama, Y., Levine, M.A., Katz, A., Gautam, N. and Nishimoto, I., 1997. G protein complex-mediated apoptosis by familial Alzheimer's disease mutant of APP. EMBO J 16, pp. 4897°4907 b. Abstract |  $Order Document

Gillian, A.M., McFarlane, I., Lucy, F.M., Overly, C.C., McConlogue, L. and Breen, K.C., 1997. The individual isoforms of the amyloid precursor protein demonstrate differential adhesive potentials to specific elements of the extracellular matrix. J Neurosci Res 49, pp. 154°160. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document | CrossRef

Giovannelli, L., Scali, C., FaussonePellegrini, M.S., Pepeu, G. and Casamenti, F., 1998. Long-term changes in the aggregation state and toxic effects of -amyloid injected into the rat brain. Neuroscience 87, pp. 349°357. SummaryPlus | Article | Journal Format-PDF (1144 K)

Giulian, D., Haverkamp, L.J., Yu, J.H., Karshin, W., Tom, D., Li, J., Kirkpatrick, J., Kuo, Y.M. and Roher, A.E., 1996. Specific domains of -amyloid from Alzheimer plaque elicit neuron killing in human microglia. J Neurosci 16, pp. 6021°6037. Abstract |  $Order Document

Glenner, G.G. and Wong, C.W., 1984. Alzheimer's disease: initial report of the purification and characterisation of a novel cerebrovascular amyloid protein. Biochem Biophys Res. Commun 120, pp. 885°890. EMBASE | BIOTECHNOBASE |  $Order Document

Goate, A., Chartierharlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericakvance, M., Roses, A., Williamson, R., Rossor, M., Owen, M. and Hardy, J., 1991. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, pp. 704°706. EMBASE |  $Order Document

Goedert, M., Trojanowski, J.Q. and Lee, V.M.-Y., 1997. The neurofibrillary pathology of Alzheimer's disease. In: Pruisner, S.B., Rosenberg, R.N., DiMauro, S. and Barchi, R.L. Editors, 1997. The Molecular and Genetic Basis of Neurological Disease Butterworth Heinemann Press, Boston, pp. 613°627.

Golde, T.E., Estus, S., Younkin, L.H., Selkoe, D.J. and Younkin, S.G., 1992. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255, pp. 728°730. EMBASE |  $Order Document

Goodman, Y. and Mattson, M.P., 1994. Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exp Neurol 128, pp. 1°12. Abstract |  $Order Document

Goodman, Y.D., Bruce, A.J., Cheng, B. and Mattson, M.P., 1996. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem 66, pp. 1836°1844. Abstract |  $Order Document

Govoni, S., Berganaschi, S., Gasparni, L., Quaglia, C., Racchi, M., Cattaneo, E., Bretti, G., Bianchesti, A., Giovetti, F., Battani, F. and Trabucchi, M., 1996. Fibroblasts of patients affected by Down's syndrome oversecrete amyloid precursor protein and are hyporesponsive to protein kinase C stimulation. Neurology 47, pp. 1069°1075. Abstract |  $Order Document

Gray, C.W. and Patel, A.J., 1993. Regulation of amyloid precursor protein isoform mRNAs by transforming growth factor-1 and interleukin-1 in astrocytes. Mol Brain Res 19, pp. 251°256. Abstract |  $Order Document

Green, P.S., Gridley, K.E. and Simpkins, J.W., 1996. Estradiol protects against amyloid (25°35)-induced toxicity in SK-N-SH human neuroblastoma cells. Neurosci Lett 218, pp. 165°168. SummaryPlus | Article | Journal Format-PDF (113 K)

Greenamyre, J.T. and Maragos, W.F., 1993. Neurotransmitter receptors in Alzheimer's disease. Cerebrovasc Brain Metab Rev 5, pp. 61°94. BIOSIS Previews |  $Order Document

Greenfield, J.P., Tsai, J., Gouras, G.K., Hai, B., Thinakaran, G., Checler, F., Sisodia, S.S., Greengard, P. and Xu, H.X., 1999. Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc Natl Acad Sci USA 96, pp. 742°747. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Gridley, K.E., Green, P.S. and Simpkins, J.W., 1998. A novel, synergistic interaction between 17 beta-estradiol and glutathione in the protection of neurons against beta-amyloid 25°35-induced toxicity in vitro. Mol Pharmacol 54, pp. 874°880. Abstract |  $Order Document

Guenette, S.Y., Chen, J., Jondro, P.D. and Tanzi, R.E., 1996. Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein. Proc Natl Acad Sci USA 93, pp. 10832°10837. BIOSIS Previews | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Guillaume, D., Bertrand, P., Dea, D., Davignon, J. and Poirier, J., 1996. Apolipoprotein E and low-density lipoprotein binding and internalization in primary cultures of rat astrocytes: isoform-specific alterations. J Neurochem 66, pp. 2410°2418. Abstract |  $Order Document

Guo, Q., Sopher, B.L., Furukawa, K., Pham, D.G., Robinson, N., Martin, G.M. and Mattson, M.P., 1997. Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: involvement of calcium and oxyradicals. J Neurosci 17, pp. 4212°4222. BIOSIS Previews | EMBASE |  $Order Document

Guo, Q., Christakos, S., Robinson, N. and Mattson, M.P., 1998. Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function. Proc Natl Acad Sci USA 95, pp. 3227°3232. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Guo, Q., Fu, W.M., Sopher, B.L., Miller, M.W., Ware, C.B., Martin, G.M. and Mattson, M.P., 1999. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5, pp. 101°106 a. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Guo, Q., Sebastian, L., Sopher, B.L., Miller, M.W., Ware, C.B., Martin, G.M. and Mattson, M.P., 1999. Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity: central roles of superoxide production and caspase activation. J Neurochem 72, pp. 1019°1029 b. Abstract |  $Order Document

Haass, C., 1996. Presenile because of presenilin°°the presenilin genes and early-onset Alzheimer's disease. Curr Opin Neurol 9, pp. 254°259. BIOSIS Previews | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Haass, C., Koo, E.H., Mellon, A., Hung, A.Y. and Selkoe, D.J., 1992. Targeting of cell surface -amyloid precursor protein to lysosomes°°alternative processing into amyloid-bearing fragments. Nature 357, pp. 500°503 a. EMBASE |  $Order Document

Haass, C., Schlossmacher, M.G., Hung, A.Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B.L., Lieberberg, I., Koo, E.H., Schenk, D., Teplow, D.B. and Selkoe, D., 1992. Amyloid -peptide is produced by cultured cells during normal metabolism. Nature 359, pp. 322°325 b. EMBASE | BIOTECHNOBASE |  $Order Document

Haass, C., Hung, A.V., Schlossmacher, M.G., Teplow, D.B. and Selkoe, D.J., 1993. Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem 268, pp. 3021°3024. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Hardy, J., 1997. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci 20, pp. 154°159. SummaryPlus | Article | Journal Format-PDF (489 K)

Harris, M.E., Wang, Y.N., Pedigo, N.W., Hensley, K., Butterfield, D.A. and Carney, J.M., 1996. Amyloid peptide (25°35) inhibits Na+-dependent glutamate uptake in rat hippocampal astrocyte cultures. J Neurochem 67, pp. 277°286. Abstract |  $Order Document

Harris-White, M.E., Chu, T., Balverde, Z., Sigel, J.J., Flanders, K.C. and Frautschy, S.A., 1998. Effects of transforming growth factor-beta (isoforms 1°3) on amyloid-beta deposition, inflammation, and cell targeting in organotypic hippocampal slice cultures. J Neurosci 18, pp. 10366°10374. Abstract |  $Order Document

Hartley, D.M., Walsh, D.M., Ye, C.P., Diehl, T., Vasquez, S., Vassilev, P.M., Teplow, D.B. and Selkoe, D.J., 1999. Protofibrillar intermediates of amyloid protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19, pp. 8876°8884. Abstract |  $Order Document

Hartmann, T., Bergsdorf, C., Sandbrink, R., Tienari, P.J., Multhaup, G., Ida, N., Bieger, S., Dyrks, T., Weidemann, A., Masters, C.L. and Beyreuther, K., 1996. Alzheimer's disease beta A4 protein release and amyloid precursor protein sorting are regulated by alternative splicing. J Biol Chem 271, pp. 13208°13214. Abstract |  $Order Document

Hartmann, T., Bieger, S.C., Bruhl, B., Tienari, P.J., Ida, N., Allsop, D., Roberts, G.W., Masters, C.L., Dotti, C.G., Unsicker, K. and Beyreuther, K., 1997. Distinct sites of intracellular production for Alzheimer's disease A40/42 amyloid peptides. Nat Med 3, pp. 1016°1020. BIOSIS Previews | EMBASE |  $Order Document

He, X.Y., Schulz, H. and Yang, S.Y., 1998. A human brain L-3-hydroxyacyl coenzyme A dehydrogenase is identical to an amyloid p-peptide-binding protein involved in Alzheimer's disease. J Biol Chem 273, pp. 10741°10746. Abstract |  $Order Document

Ho, L.B., Fukuchi, K. and Younkin, S.G., 1996. The alternatively spliced Kunitz protease inhibitor domain alters amyloid beta protein precursor processing and amyloid beta protein production in cultured cells. J Biol Chem 271, pp. 30929°30934. Abstract |  $Order Document

Holcomb, L., Gordon, M.N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., Ocampo, K., Hardy, J., Prada, C.M., Eckman, C., Younkin, S., Hsiao, K. and Duff, K., 1998. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4, pp. 97°100. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Holtzman, D.M., Pitas, R.E., Kilbridge, J., Nathan, B., Mahley, R.W., Bu, G.J. and Schwartz, A.L., 1995. Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc Natl Acad Sci USA 92, pp. 9480°9484. BIOSIS Previews |  $Order Document

Howell, B.W., Gertler, F.B. and Cooper, J.A., 1997. Mouse disabled (mDab1): a Src binding protein implicated in neuronal development. EMBO J 16, pp. 121°132 a. Abstract |  $Order Document

Howell, B.W., Hawkes, R., Soriano, P. and Cooper, J.A., 1997. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389, pp. 733°737 b. BIOSIS Previews | EMBASE |  $Order Document

Howland, D.S., Trusko, S.P., Savage, M.J., Reaume, A.G., Lang, D.M., Hirsch, J.D., Maeda, N., Siman, R., Greenberg, B.D., Scott, R.M. and Flood, D.G., 1998. Modulation of secreted beta-amyloid precursor protein and amyloid beta peptide in brain by cholesterol. J Biol Chem 273, pp. 16576°16582. Abstract |  $Order Document

Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F. and Cole, G., 1996. Correlative memory deficits, A elevation and amyloid plaques in transgenic mice. Science 274, pp. 99°102. BIOSIS Previews | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Hu, Q.B., Kukull, W.A., Bressler, S.L., Gray, M.D., Cam, J.A., Larson, E.B., Martin, G.M. and Deeb, S.S., 1998. The human FE65 gene: genomic structure and an intronic biallelic polymorphism associated with sporadic dementia of the Alzheimer type. Hum Genet 103, pp. 295°303. Abstract |  $Order Document

Huang, H.M., Ou, H.C. and Hsueh, S.J., 1998. Amyloid beta peptide enhanced bradykinin-mediated inositol (1,4,5)-trisphosphate formation and cytosolic free calcium. Life Sci 63, pp. 195°203 a. Abstract | Journal Format-PDF (452 K)

Huang, S.S., Huang, F.W., Xu, J., Chan, S.W., Hsu, C.Y. and Huang, J.S., 1998. Amyloid beta peptide possesses a transforming growth factor- activity. J Biol Chem 273, pp. 27640°27644 b. BIOSIS Previews |  $Order Document

Huber, G., Bailly, Y., Martin, J.R., Mariani, J. and Brugg, B., 1997. Synaptic -amyloid precursor proteins increase with learning capacity in rats. Neuroscience 80, pp. 313°320. SummaryPlus | Article | Journal Format-PDF (273 K)

Hughes, S.R., Khorkova, O., Goyal, S., Knaeblein, J., Heroux, J., Riedel, N.G. and Sahasrabudhe, S., 1998. Alpha(2)-macroglobulin associates with beta-amyloid peptide and prevents fibril formation. Proc Natl Acad Sci USA 95, pp. 3275°3280. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Hull, M., Strauss, S., Berger, M. and Volk, B., 1996. Inflammatory mechanisms in Alzheimer's-disease. Eur Arch Psychiatry Clin Neurosci 246, pp. 124°128. Abstract |  $Order Document

Hulme, E.C., Birdsall, N.J.M. and Buckley, N.J., 1990. Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 30, pp. 633°673. EMBASE | BIOTECHNOBASE |  $Order Document

Ibarreta, D., Duchen, M., Ma, D.W., Qiao, L.X., Kozikowski, A.P. and Etcheberrigaray, R., 1999. Benzolactam (BL) enhances sAPP secretion in fibroblasts and in PC12 cells. Neuroreport 10, pp. 1035°1040. Abstract |  $Order Document

Ikezu, T., Okamoto, T., Komatsuzaki, K., Matsui, T., Martyn, J.A.J. and Nishimoto, I., 1996. Negative transactivation of cAMP response element by familial Alzheimer's mutants of APP. EMBO J 15, pp. 2468°2475. Abstract |  $Order Document

Ikezu, T., Trapp, B.D., Song, K.S., Schlegel, A., Lisanti, M.P. and Okamoto, T., 1998. Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein. J Biol Chem 273, pp. 10485°10495. Abstract |  $Order Document

Ishida, A., Furukawa, K., Keller, J.N. and Mattson, M.P., 1997. Secreted form of -amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices. Neuroreport 8, pp. 2133°2137. Abstract |  $Order Document

Itagaki, S., McGeer, P.L., Akiyama, H., Zhu, S. and Selkoe, D., 1989. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer's disease. J Neuroimmunol 24, pp. 173°182.

Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N. and Ihara, Y., 1994. Visualization of A-42(43) and A-40 in senile plaques with end-specific A monoclonals°°evidence that an initially deposited species is A-42(43). Neuron 13, pp. 45°53. Abstract |  $Order Document

Iwatsubo, T., Mann, D.M.A., Odaka, A., Suzuki, N. and Ihara, Y., 1995. Amyloid- protein (A) deposition°°A42(43) precedes A40 in Down's syndrome. Ann Neurol 37, pp. 294°299. Abstract |  $Order Document

Jacobsen, J.S., Spruyt, M.A., Brown, A.M., Sahasrabudhe, S.R., Blume, A.J., Vitek, M.P., Muenkel, H.A. and Sonnenbergreines, J., 1994. The release of Alzheimer's disease -amyloid peptide is reduced by phorbol treatment. J Biol Chem 269, pp. 8376°8382. Abstract |  $Order Document

Jaffe, A.B., Toranallerand, C.D., Greengard, P. and Gandy, S.E., 1994. Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem 269, pp. 13065°13068. Abstract |  $Order Document

Jarrett, J.T. and Lansbury, P.T., 1993. Seeding "one dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie?. Cell 73, pp. 1055°1058. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Jiang, H.X., Burdick, D., Glabe, C.G., Cotman, C.W. and Tenner, A.J., 1994. Beta-amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q alpha chain. J Immunol 152, pp. 5050°5059. Abstract |  $Order Document

Jin, L.W., Ninomiya, H., Roch, J.M., Schubert, D., Masliah, E., Otero, D.A.C. and Saitoh, T., 1994. Peptides containing the RERMS sequence of amyloid A4 protein precursor bind cell surface and promote neurite extension. J Neurosci 14, pp. 5461°5470. Abstract |  $Order Document

Jockusch, B.M., Bubeck, P., Giehl, K., Kroemker, M., Moschner, J., Rothkegel, M., Rudiger, M., Schluter, K., Stanke, G. and Winkler, J., 1995. The molecular architecture of focal adhesions. Annu Rev Cell Dev Biol 11, pp. 379°416. BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document

Johnson, S.A., McNeill, T., Cordell, B. and Finch, C.E., 1990. Relation of neuronal APP-751/APP-695 messenger RNA ratio and neuritic plaque density in Alzheimer's disease. Science 248, pp. 854°857. BIOTECHNOBASE | EMBASE |  $Order Document

Jolly-Tornetta, C., Gao, Z.Y., Lee, V.M.Y. and Wolf, B.A., 1998. Regulation of amyloid precursor protein seer receptors in human Ntera 2 neurons (NT2N). J Biol Chem 273, pp. 14015°14021. Abstract |  $Order Document

Jope, R.S., Song, L. and Powers, R.E., 1997. Cholinergic activation of phosphoinositide signaling is impaired in Alzheimer's disease brain. Neurobiol Aging 18, pp. 111°120. SummaryPlus | Article | Journal Format-PDF (307 K)

Jordan, J., Galindo, M.F., Miller, R.J., Reardon, C.A., Getz, G.S. and LaDu, M.J., 1998. Isoform-specific effect of apolipoprotein E on cell survival and amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J Neurosci 18, pp. 195°204. Abstract |  $Order Document

Joseph, R. and Han, E., 1992. Amyloid -protein fragment 25°35 causes activation of cytoplasmic calcium in neurons. Biochem Biophys Res Commun 184, pp. 1441°1447. BIOTECHNOBASE | EMBASE |  $Order Document

Kammesheidt, A., Boyce, F.M., Spanoyannis, A.F., Cummings, B.J., Ortegon, M., Cotman, C., Vaught, J.L. and Neve, R.L., 1992. Deposition of A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl terminal fragment of the Alzheimer amyloid precursor in the brain. Proc Natl Acad Sci USA 89, pp. 10857°10861. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Kanemaru, K., Meckelein, B., Marshall, D.C.L., Sipe, J.D. and Abraham, C.R., 1996. Synthesis and secretion of active alpha(1)-antichymotrypsin by murine primary astrocytes. Neurobiol Aging 17, pp. 767°771. SummaryPlus | Article | Journal Format-PDF (438 K)

Kang, J., Lemaire, H., Unterbeck, A., Salbaum, J.M., Masters, C.L., Grzeschik, K., Multhaup, G., Beyreuther, K. and Muller-Hill, B., 1987. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, pp. 733°736. BIOTECHNOBASE | EMBASE |  $Order Document

Kar, S., Issa, A.M., Seto, D., Auld, D.S., Collier, B. and Quirion, R., 1998. Amyloid -peptide inhibits high-affinity choline uptake and acetylcholine release in rat hippocampal slices. J Neurochem 70, pp. 2179°2187. Abstract |  $Order Document

Keller, J.N., Pang, Z., Geddes, J.W., Begley, J.G., Germeyer, A., Weng, G. and Mattson, M.P., 1997. Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid -peptide: role of the lipid peroxidation product 4-hydroxynonenal. J Neurochem 69, pp. 273°284. Abstract |  $Order Document

Keller, J.N., Guo, Q., Holtsberg, F.W., Bruce-Keller, A.J. and Mattson, M.P., 1998. Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. J Neurosci 18, pp. 4439°4450. Abstract |  $Order Document

Kelliher, M., Fastbom, J., Cowburn, R.F., Bonkale, W., Ohm, T.G., Ravid, R., Sorrento, V. and O'Neill, C., 1999. Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer's disease neurofibrillary and -amyloid pathologies. Neuroscience 92, pp. 499°513. SummaryPlus | Article | Journal Format-PDF (271 K)

Kelly, J.F., Furukawa, K., Barger, S.W., Rengen, M.R., Mark, R.J., Blanc, E.M., Roth, G.S. and Mattson, M.P., 1996. Amyloid -peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons. Proc Natl Acad Sci USA 93, pp. 6753°6758. BIOSIS Previews | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Khalil, Z., Sanderson, K., Isberg, P., Bassirat, M., Livett, B. and Helme, R., 1994. A4(25°35) modulates substance-P effect on rat skin microvasculature in aged rats°°pharmacological manipulation using SEC-receptor ligands. Brain Res 651, pp. 227°235. Abstract |  $Order Document

Kibbey, M.C., Jucker, M., Weeks, B.S., Neve, R.L., Van Nostrand, W.E. and Kleinmann, H.K., 1993. -Amyloid precursor protein binds to the neurite-promoting IKVAV site of laminin. Proc Natl Acad Sci USA 90, pp. 10150°10153. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Kim, S.H. and Suh, Y.H., 1996. Neurotoxicity of a carboxyl-terminal fragment of the Alzheimer's amyloid precursor protein. J Neurochem 67, pp. 1172°1182. Abstract |  $Order Document

Kim, S.H., Kim, Y.K., Jeong, S.J., Haass, C., Kim, Y.H. and Suh, Y.H., 1997. Enhanced release of secreted form of Alzheimer's amyloid precursor protein from PC12 cells by nicotine. Mol Pharmacol 52, pp. 430°436. Abstract |  $Order Document

Kim, H.S., Park, C.H. and Suh, Y.H., 1998. C-terminal fragment of amyloid precursor protein inhibits calcium uptake into rat brain microsomes by Mg2+-Ca2+ ATPase. Neuroreport 9, pp. 3875°3879. Abstract |  $Order Document

Kim, H.S., Lee, J.H. and Suh, Y.H., 1999. C-terminal fragment of Alzheimer's amyloid precursor protein inhibits sodium/calcium exchanger activity in SK-N-SH cell. Neuroreport 10, pp. 113°116. Abstract |  $Order Document

Kimura, H. and Schubert, D., 1993. Amyloid protein activates tachykinin receptors and inositol triphosphate accumulation by synergy with glutamate. Proc Natl Acad Sci USA 90, pp. 7508°7512. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Kinouchi, T., Sorimachi, H., Maruyama, K., Mizuno, K., Ohno, S., Ishiura, S. and Suzuki, K., 1995. Conventional protein kinase (PKC)-alpha and novel PKC-epsilon, but not PKC-delta, increase the secretion of an N-terminal fragment of Alzheimer's disease amyloid precursor protein from PKC cDNA transfected 3Y1 fibroblasts. FEBS Lett 364, pp. 203°206. Abstract | Journal Format-PDF (462 K)

Kitaguchi, N., Takahashi, Y., Tokushima, Y., Shiojiri, S. and Ito, H., 1988. Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature 331, pp. 530°532. BIOTECHNOBASE | EMBASE |  $Order Document

Klafki, H.W., Paganetti, P.A., Sommer, B. and Staufenbiel, M., 1995. Calpain inhibitor I decreases A4 secretion from human embryonal kidney cells expressing amyloid precursor protein carrying the APP670/671 double mutation. Neurosci Lett 201, pp. 29°32. Abstract | Journal Format-PDF (432 K)

Klier, F.G., Cole, G., Stallcup, W. and Schubert, D., 1990. Amyloid -protein precursor is associated with extracellular matrix. Brain Res 515, pp. 336°342. EMBASE |  $Order Document

Koo, E.H., 1997. Phorbol esters affect multiple steps in -amyloid precursor protein trafficking and amyloid -protein production. Mol Med 3, pp. 204°211. BIOSIS Previews | EMBASE |  $Order Document

Koo, E.H. and Squazzo, S.L., 1994. Evidence that production and release of amyloid -protein involves the endocytic pathway. J Biol Chem 269, pp. 17386°17389. Abstract |  $Order Document

Koo, E.H., Park, L. and Selkoe, D.J., 1993. Amyloid -protein as a substrate interacts with extracellular matrix to promote neurite outgrowth. Proc Natl Acad Sci USA 90, pp. 4748°4752. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Koo, E.H., Squazzo, S.L., Selkoe, D.J. and Koo, C.H., 1996. Trafficking of cell-surface amyloid beta-protein precursor. 1. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody. J Cell Sci 109, pp. 991°998. Abstract |  $Order Document

Korotzer, A.R., Pike, C.J. and Cotman, C.W., 1993. Amyloid peptides induce degeneration of cultured rat microglia. Brain Res 624, pp. 121°125. Abstract |  $Order Document

Korotzer, A.R., Whittemore, E.R. and Cotman, C.W., 1995. Differential regulation by -amyloid peptides of intracellular free Ca2+ concentration in cultured rat microglia. Eur J Pharmacol 288, pp. 125°130. Abstract |  $Order Document

Kounnas, M.Z., Moir, R.D., Rebeck, G.W., Bush, A.I., Argraves, W.S., Tanzi, R.E., Hyman, B.T. and Strickland, D.K., 1995. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted -amyloid precursor protein and mediates its degradation. Cell 82, pp. 331°340. Abstract |  $Order Document

Kowall, N.W., Beal, M.F., Busciglio, J., Duffy, L.K. and Yankner, B.A., 1991. An in vivo model for the neurodegenerative effect of amyloid and protection by substance P. Proc Natl Acad Sci USA 88, pp. 7247°7251. BIOTECHNOBASE | EMBASE |  $Order Document

Kozlowski, M.R., Spanoyannis, A., Manly, S.P., Fidel, S.A. and Neve, R.L., 1992. The neurotoxic carboxy-terminal fragment of the Alzheimer amyloid precursor binds specifically to a neuronal cell surface molecule: pH dependence of the neurotoxicity and the binding. J Neurosci 12, pp. 1679°1687. EMBASE |  $Order Document

Kumar, U., Dunlop, D.M. and Richardson, J.S., 1994. Mitochondria from Alzheimer's fibroblasts show decreased uptake of calcium and increased sensitivity to free radicals. Life Sci 54, pp. 1855°1860. Abstract |  $Order Document

Kuner, P., Schubenel, R. and Hertel, C., 1998. -Amyloid binds to p75(NTR) and activates NF kappa B in human neuroblastoma cells. J Neurosci Res 54, pp. 798°804. BIOSIS Previews | EMBASE |  $Order Document | CrossRef

Lahiri, D.K., 1994. Effect of ionophores on the processing of the -amyloid precursor protein in different cell lines. Cell Mol Neurobiol 14, pp. 297°313 a. Abstract |  $Order Document

Lahiri, D.K., 1994. Reversibility of the effect of tacrine on the secretion of the -amyloid precursor protein in cultured cells. Neurosci Lett 181, pp. 149°152 b. Abstract |  $Order Document

Lai, A., Sisodia, S.S. and Trowbridge, I.S., 1995. Characterization of sorting signals in the -amyloid precursor protein cytoplasmic domain. J Biol Chem 270, pp. 3565°3573. Abstract |  $Order Document

Lai, A., Gibson, A., Hopkins, C.R. and Trowbridge, I.S., 1998. Signal-dependent trafficking of beta-amyloid precursor protein-transferrin receptor chimeras in Madin-Darby canine kidney cells. J Biol Chem 273, pp. 3732°3739. Abstract |  $Order Document

Lamb, B.T., Call, L.M., Slunt, H.H., Bardel, K.A., Lawler, A.M., Eckman, C.B., Younkin, S.G., Holtz, G., Wagner, S.L., Price, D.L., Sisodia, S.S. and Gearhart, J.D., 1997. Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice. Hum Mol Genet 6, pp. 1535°1541. Abstract |  $Order Document

Lambert, M.P., Barlow, A.K., Chromy, B.A., Edwards, C., Freed, R., Liosatos, M., Morgan, T.E., Rozovsky, I., Trommer, B., Viola, K.L., Wals, P., Zhang, C., Finch, C.E., Krafft, G.A. and Klein, W.L., 1998. Diffusible, nonfibrillar ligands derived from A1°42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95, pp. 6448°6453. BIOSIS Previews | BIOTECHNOBASE | EMBASE | Elsevier BIOBASE |  $Order Document

Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., Jasionowski, M., Haass, C. and Fahrenholz, F., 1999. Constitutive and regulated -secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA 96, pp. 3922°3929.

Lansbury, P.T., 1995. Consequences of the molecular mechanism of amyloid formation for the understanding of the pathogenesis of Alzheimer's disease and the development of therapeutic strategies. Drug Res 45, pp. 432°434. BIOSIS Previews | Beilstein Abstracts |  $Order Document

Launer, L.J., Fratiglioni, L., Andersen, K., Breteler, M.M.B., Copeland, R.J.M., Dartigues, J.-F., Lobo, A., Martinez-Lage, J., Soininen, H. and Hofman, A., 1999. Regional differences in the incidence of dementia in Europe°°EURODEM collaborative analysis. In: Iqbal, K., Swaab, D.F., Winblad, B. and Wisniewski, H.M. Editors, 1999. Alzheimer's Disease and Related Disorders: Etiology, Pathogenesis and Therapeutics John Wiley & Sons, New York, pp. 9°15.

Le, W.D., Xie, W.J., Nyormoi, O., Ho, B.K., Smith, R.G. and Appel, S.H., 1995. -Amyloid(1°40) increases expression of a-amyloid precursor protein in neuronal hybrid cells. J Neurochem 65, pp. 2373°2376. Abstract |  $Order Document

Le, W.D., Xie, W.J., Kong, R. and Appel, S.H., 1997. -Amyloid-induced neurotoxicity of a hybrid septal cell line associated with increased tau phosphorylation and expression of beta-amyloid precursor protein. J Neurochem 69, pp. 978°985. Abstract |  $Order Document

Leanza, G., 1998. Chronic elevation of amyloid precursor protein expression in the neocortex and hippocampus of rats with selective cholinergic lesions. Neurosci Lett 257, pp. 53°56. SummaryPlus | Article | Journal Format-PDF (521 K)

LeBlanc, A.C. and Goodyer, C.G., 1999. Role of endoplasmic reticulum, endosomal-lysosomal compartments, and microtubules in amyloid precursor protein metabolism of human neurons. J Neurochem 72, pp. 1832°1842. Abstract |  $Order Document

LeBlanc, A.C., Koutroumanis, M. and Goodyer, C.G., 1998. Protein kinase C activation increases release of secreted amyloid precursor protein without decreasing A beta production in human primary neuron cultures. J Neurosci 18, pp. 2907°2913. Abstract |  $Order Document

Ledesma, M.D., Bonnay, P., Colaco, C. and Avila, J., 1994. Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem 269, pp. 21614°21619. Abstract |  $Order Document

Lee, R.K.K. and Wurtman, R.J., 1997. Metabotropic glutamate receptors increase amyloid precursor protein processing in astrocytes: inhibition by cyclic AMP. J Neurochem 68, pp. 1830°1835. BIOSIS Previews | EMBASE |  $Order Document

Lee, R.K.K., Wurtman, R.J., Cox, A.J. and Nitsch, R.M., 1995. Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. Proc Natl Acad Sci USA 92, pp. 8083°8087. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Lee, R.K.K., Knapp, S. and Wurtman, R.J., 1999. Prostaglandin E-2 stimulates amyloid precursor protein gene expression: inhibition by immunosuppressants. J Neurosci 19, pp. 940°947. Abstract |  $Order Document

Lehtonen, J.Y.A., Holopainen, J.M. and Kinnunen, P.K.J., 1996. Activation of phospholipase A2 by amyloid -peptides in vitro. Biochemistry 35, pp. 9407°9414. Abstract |  $Order Document

Leissring, M.A., Paul, B.A., Parker, I., Cotman, C.W. and LaFerla, F.M., 1999. Alzheimer's presenilin-1 mutation potentiates inositol 1,4,5-triphosphate-mediated calcium signaling in Xenopus oocytes. J Neurochem 72, pp. 1061°1068. Abstract |  $Order Document

Lemere, C.A., Lopera, F., Kosik, K.S., Lendon, C.L., Ossa, J., Saido, T.C., Yamaguchi, H., Ruiz, A., Martinez, A., Madrigal, L., Hincapie, L., Arango, J.C.L., Anthony, D.C., Koo, E.H., Goate, A.M., Selkoe, D.J. and Arango, J.C.V., 1996. The E280A presenilin-1 Alzheimer mutation produces increased A42 deposition and severe cerebellar pathology. Nat Med 2, pp. 1146°1150. Elsevier BIOBASE |  $Order Document

Leveugle, B. and Fillit, H., 1994. Proteoglycans and the acute-phase response in Alzheimer's-disease brain. Mol Neurobiol 9, pp. 25°32. BIOSIS Previews |  $Order Document

Leveugle, B., Ding, W.H., Laurence, F., Dehouck, M.P., Scanameo, A., Cecchelli, R. and Fillit, H., 1998. Heparin oligosaccharides that pass the blood-brain barrier inhibit beta-amyloid precursor protein secretion and heparin binding to beta-amyloid peptide. J Neurochem 70, pp. 736°744. Abstract |  $Order Document

Levy, E., Carman, M.D., Fernandezmadrid, I.J., Power, M.D., Lieberburg, I., Vanduinen, S.G., Bots, G., Luyendijk, W. and Frangione, B., 1990. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, pp. 1124°1126. EMBASE | BIOTECHNOBASE |  $Order Document

Lezoualch, F., Sagara, Y., Holsboer, F. and Behl, C., 1998. High constitutive NF-kappa B activity mediates resistance to oxidative stress in neuronal cells. J Neurosci 18, pp. 3224°3232. Abstract |  $Order Document

Li, S.W., Okamoto, T., Chun, M.Y., Sargiacomo, M., Casanova, J.E., Hansen, S.H., Nishimoto, I. and Lisanti, M.P., 1995. Evidence for a regulated interaction between heterotrimeric G-proteins and caveolin. J Biol Chem 270, pp. 15693°15701. Abstract |  $Order Document

Li, X.J. and Greenwald, I., 1998. Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc Natl Acad Sci USA 95, pp. 7109°7114. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Liao, A., Nitsch, R.M., Greenberg, S.M., Finckh, U., Blacker, D., Albert, M., Rebeck, G.W., GomezIsla, T., Clatworthy, A., Binetti, G., Hock, C., MuellerThomsen, T., Mann, U., Zuchowski, K., Beisiegel, U., Staehelin, H., Growdon, J.H., Tanzi, R.E. and Hyman, B.T., 1998. Genetic association of an alpha 2-macroglobulin (Val1000Ile) polymorphism and Alzheimer's disease. Hum Mol Genet 7, pp. 1953°1956. Abstract |  $Order Document

Lisanti, M.P., Scherer, P.E., Vidugiriene, J., Tang, Z.L., Hermanowskivosatka, A., Tu, Y.H., Cook, R.F. and Sargiacomo, M., 1994. Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source°°implications for human disease. J Cell Biol 126, pp. 111°126. Abstract |  $Order Document

Liu, P.S. and Anderson, R.G.W., 1995. Compartmentalized production of ceramide at the cell surface. J Biol Chem 270, pp. 27179°27185. Abstract |  $Order Document

Liu, P.S., Ying, Y.S., Ko, Y.G. and Anderson, R.G.W., 1996. Localization of platelet-derived growth factor-stimulated phosphorylation cascade to caveolae. J Biol Chem 271, pp. 10299°10303. Abstract |  $Order Document

Liu, Y., Peterson, D.A. and Schubert, D., 1998. Amyloid peptide alters intracellular vesicle trafficking and cholesterol homeostasis. Proc Natl Acad Sci USA 95, pp. 13266°13271. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Loffler, J. and Huber, G., 1993. Modulation of amyloid precursor protein secretion in differentiated and non-differentiated cells. Biochem Biophys Res Commun 195, pp. 97°103. Abstract |  $Order Document | CrossRef

Lorenzo, A. and Yankner, B.A., 1994. Beta amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc Natl Acad Sci USA 91, pp. 12243°12247. BIOSIS Previews | EMBASE | BIOTECHNOBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Lorton, D., 1997. Amyloid-induced IL-1 beta release from an activated human monocyte cell line is calcium- and G-protein-dependent. Mech Ageing Dev 94, pp. 199°211. SummaryPlus | Article | Journal Format-PDF (487 K)

Lorton, D., Kocsis, J.M., King, L., Madden, K. and Brunden, K.R., 1996. -Amyloid induces increased release of interleukin-1 from lipopolysaccharide-activated human monocytes. J Neuroimmunol 67, pp. 21°29. SummaryPlus | Article | Journal Format-PDF (590 K)

Luo, Y.Q., Hirashima, N., Ann, H., Li, Y.H., Alkon, D.L., Sunderland, T., Etcheberrigaray, R. and Wolozin, B., 1995. Physiological levels of -amyloid increase tyrosine phosphorylation and cytosolic calcium. Brain Res 681, pp. 65°74. Abstract | Journal Format-PDF (757 K)

Luo, Y., Sunderland, T. and Wolozin, B., 1996. Physiologic levels of amyloid activate phosphatidylinositol 3 kinase with the involvement of tyrosine phosphorylation. J Neurochem 67, pp. 978°987. Abstract |  $Order Document

Luo, Y., Hawver, D.B., Iwasaki, K., Sunderland, T., Roth, G.S. and Wolozin, B., 1997. Physiological levels of -amyloid peptide stimulate protein kinase C in PC12 cells. Brain Res 769, pp. 287°295. SummaryPlus | Article | Journal Format-PDF (250 K)

Mackenzie, I.R.A., Hao, C.H. and Munoz, D.G., 1995. Role of microglia in senile plaque formation. Neurobiol Aging 16, pp. 797°804. Abstract | Journal Format-PDF (752 K)

Malarkey, K., Belham, C.M., Paul, A., Graham, A., McLees, A., Scott, P.H. and Plevin, R., 1995. The regulation of tyrosine kinase signaling pathways by growth factor and G-protein-coupled receptors. Biochem J 309, pp. 361°375. Abstract |  $Order Document

Marambaud, P., Chevallier, N., Barelli, H., Wilk, S. and Checler, F., 1997. Proteasome contributes to the alpha secretase pathway of amyloid precursor protein in human cells. J Neurochem 68, pp. 688°703 a.

Marambaud, P., LopezPerez, E., Wilk, S. and Checler, F., 1997. Constitutive and protein kinase C-regulated secretory cleavage of Alzheimer's -amyloid precursor protein: different control of early and late events by the proteasome. J Neurochem 69, pp. 2500°2505 b. Abstract |  $Order Document

Marambaud, P., Ancolio, K., daCosta, C.A. and Checler, F., 1999. Effect of protein kinase A inhibitors on the production of A beta 40 and A beta 42 by human cells expressing normal and Alzheimer's disease-linked mutated beta APP and presenilin 1. Br J Pharmacol 126, pp. 1186°1190. Abstract |  $Order Document

Marcon, G., Giaccone, G., Canciani, B., Cajola, L., Rossi, G., DeGioia, L., Salmona, M., Bugiani, O. and Tagliavini, F., 1999. A beta PP peptide carboxyl-terminal to A beta is neurotoxic. Am J Pathol 154, pp. 1001°1007. Abstract |  $Order Document

Maresh, G.A., Erezyilmaz, D., Murry, C.E., Nochlin, D. and Snow, A.D., 1996. Detection and quantitation of perlecan mRNA levels in Alzheimer's disease and normal aged hippocampus by competitive reverse transcription-polymerase chain reaction. J Neurochem 67, pp. 1132°1144. Abstract |  $Order Document

Mark, R.J., Hensley, K., Butterfield, D.A. and Mattson, M.P., 1995. Amyloid -peptide impairs ion-motive ATPase activities°°evidence for a role in loss of neuronal calcium homeostasis and cell death. J Neurosci 15, pp. 6239°6249. Abstract |  $Order Document

Mark, R.J., Pang, Z., Geddes, J.W., Uchida, K. and Mattson, M.P., 1997. Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J Neurosci 17, pp. 1046°1054. Abstract |  $Order Document

Mark, R.J., Fuson, K.S. and May, P.C., 1999. Characterization of 8-epiprostaglandin F-2 alpha as a marker of amyloid peptide-induced oxidative damage. J Neurochem 72, pp. 1146°1153. Abstract |  $Order Document

Marquez-Sterling, N.R., Lo, A.C.Y., Sisodia, S.S. and Koo, E.H., 1997. Trafficking of cell surface amyloid precursor protein°°evidence that a sorting intermediate participates in synaptic vesicle recycling. J Neurosci 17, pp. 140°151. BIOSIS Previews | EMBASE |  $Order Document

Masters, C.L., Simms, G., Weinman, N.A., Multhaup, G., McDonald, B.L. and Beyreuther, K., 1985. Amyloid plaque core protein in Alzheimer's disease and Down syndrome. Proc Natl Acad Sci USA 82, pp. 4245°4249. EMBASE | BIOTECHNOBASE |  $Order Document

Mattson, M.P., 1994. Secreted forms of -amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons. J Neurobiol 25, pp. 439°450. Abstract |  $Order Document

Mattson, M.P., Cheng, B., Davis, D., Bryant, K., Lieberberg, I. and Rydel, R.E., 1992. -Amyloid peptides destabilise calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12, pp. 376°389. EMBASE |  $Order Document

Mattson, M.P., Cheng, B., Culwell, A.R., Esch, F.S., Lieberberg, I. and Rydel, R.E., 1993. Evidence for excitoprotective and intraneuronal calcium regulating roles for secreted forms of the -amyloid precursor protein. Neuron 10, pp. 243°254. EMBASE |  $Order Document

Mattson, M.P., Cheng, B., Baldwin, S.A., Smith-Swintosky, V.L., Keller, J., Geddes, J., Scheff, J.W. and Christakos, S., 1995. Brain injury and tumor necrosis factors induce calbindin-D-28k in astrocytes: evidence for a cytoprotective response. J Neurosci Res 42, pp. 257°267.

Mattson, M.P., Goodman, Y., Luo, H., Fu, W.M. and Furukawa, K., 1997. Activation of NF-kappa B protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J Neurosci Res 49, pp. 681°697 a. BIOSIS Previews | EMBASE |  $Order Document | CrossRef

Mattson, M.P., Robinson, N. and Guo, Q., 1997. Estrogens stabilize mitochondrial function and protect neural cells against the pro-apoptotic action of mutant presenilin-1. Neuroreport 8, pp. 3817°3821 b. Abstract |  $Order Document

McDonald, D.R., Brunden, K.R. and Landreth, G.E., 1997. Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J Neurosci 17, pp. 2284°2294. Abstract |  $Order Document

McDonald, D.R., Bamberger, M.E., Combs, C.K. and Landreth, G.E., 1998. -Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci 18, pp. 4451°4460. Abstract |  $Order Document

McFarlane, I., Breen, K.C., DiGiamberardino, L. and Moya, K.L., 1997. Inhibition of N-glycan processing alters axonal transport in vivo. Soc Neurosci Abstr 23, p. 640. BIOSIS Previews |  $Order Document

McKee, A.C., Kowall, N.W., Schumacher, J.S. and Beal, M.F., 1998. The neurotoxicity of amyloid beta protein in aged primates. Amyloid: Int J Exp Clin Invest 5, pp. 1°9.

McLaughlin, M. and Breen, K.C., 1999. Protein kinase C activation potentiates the rapid secretion of the amyloid precursor protein from rat cortical synaptosomes. J Neurochem 72, pp. 273°281. Abstract |  $Order Document

McLoughlin, D.M. and Miller, C.C.J., 1996. The intracellular cytoplasmic domain of the Alzheimer's disease amyloid precursor protein interacts with phosphotyrosine-binding domain proteins in the yeast two-hybrid system. FEBS Lett 397, pp. 197°200. Abstract | Journal Format-PDF (324 K)

McPhie, D.L., Lee, R.K.K., Eckman, C.B., Olstein, D.H., Durham, S.P., Yager, D., Younkin, S.G., Wurtman, R.J. and Neve, R.L., 1997. Neuronal expression of beta-amyloid precursor protein Alzheimer mutations causes intracellular accumulation of a C-terminal fragment containing both the amyloid beta and cytoplasmic domains. J Biol Chem 272, pp. 24743°24746. Abstract |  $Order Document

Mecocci, P., Cherubini, A., Beal, M.F., Cecchetti, R. and Chionne, F., 1996. Altered mitochondrial membrane fluidity in AD brain. Neurosci Lett 207, pp. 129°132. Abstract | Journal Format-PDF (271 K)

Mentlein, R., Ludwig, R. and Martensen, I., 1998. Proteolytic degradation of Alzheimer's disease amyloid beta-peptide by a metalloproteinase from microglia cells. J Neurochem 70, pp. 721°726. Abstract |  $Order Document

Meziane, H., Dodart, J.-C., Mathias, C., Little, S., Clemens, J., Paul, S.M. and Ungerer, A., 1998. Memory-enhancing effects of secreted forms of the amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci USA 95, pp. 12683°12688. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Michaelis, M.L., Ranciat, N., Chen, Y., Bechtel, M., Ragan, R., Hepperle, M., Liu, Y. and Georg, G., 1998. Protection against -amyloid toxicity in primary neurons by paclitaxel (Taxol). J Neurochem 70, pp. 1623°1627. Abstract |  $Order Document

Mills, J. and Reiner, P.B., 1999. Regulation of amyloid precursor protein cleavage. J Neurochem 72, pp. 443°460. Abstract |  $Order Document

Mills, J., Charest, D.L., Lam, F., Beyreuther, K., Ida, N., Pelech, S.L. and Reiner, P.B., 1997. Regulation of amyloid precursor protein catabolism involves the mitogen-activated protein kinase signal transduction pathway. J Neurosci 17, pp. 9415°9422. Abstract |  $Order Document

Mirzabekov, T., Lin, M.C., Yuan, W.L., Marshall, P.J., Carman, M., Tomaselli, K., Lieberburg, I. and Kagan, B.L., 1994. Channel formation in planar lipid bilayers by a neurotoxic fragment of the beta-amyloid peptide. Biochem Biophys Res Commun 202, pp. 1142°1148. Abstract |  $Order Document | CrossRef

Mizuno, T., Nakata, M., Naiki, H., Michikawa, M., Wang, R., Haass, C. and Yanagisawa, K., 1999. Cholesterol-dependent generation of a seeding amyloid -protein in cell culture. J Biol Chem 274, pp. 15110°15114. Abstract |  $Order Document

Moestrup, S.K. and Gliemann, J., 1991. Analysis of ligand recognition by the purified alpha-2-macroglobulin receptor (low density lipoprotein receptor-related protein)°°evidence that high-affinity of alpha-2-macroglobulin-proteinase complex is achieved by binding to adjacent receptors. J Biol Chem 266, pp. 14011°14017. EMBASE | BIOTECHNOBASE |  $Order Document

Mok, S.S., Sberna, G., Heffernan, D., Cappai, R., Galatis, D., Clarris, H.J., Sawyer, W.H., Beyreuther, K., Masters, C.L. and Small, D.H., 1997. Expression and analysis of heparin-binding regions of the amyloid precursor protein of Alzheimer's disease. FEBS Lett 415, pp. 303°307. SummaryPlus | Article | Journal Format-PDF (613 K)

Monning, U., Sandbrink, R., Weidemann, A., Banati, R.B., Masters, C.L. and Beyreuther, K., 1995. Extracellular matrix influences the biogenesis of amyloid precursor protein in microglial cells. J Biol Chem 270, pp. 7104°7110. Abstract |  $Order Document

Morimoto, K., Yoshimi, K., Tonohiro, T., Yamada, N., Oda, T. and Kaneko, I., 1998. Co-injection of -amyloid with ibotenic acid induces synergistic loss of rat hippocampal neurons. Neuroscience 84, pp. 479°487 a. SummaryPlus | Article | Journal Format-PDF (441 K)

Morimoto, T., Ohsawa, I., Takamura, C., Ishiguro, M., Nakamura, Y. and Kohsaka, S., 1998. Novel domain-specific actions of amyloid precursor protein on developing synapses. J Neurosci 18, pp. 9386°9393 b. Abstract | Abstract |  $Order Document

Morin, P.J., Abraham, C.R., Amaratunga, A., Johnson, R.J., Huber, G., Sandell, J.H. and Fine, R.E., 1993. Amyloid precursor protein is synthesised by retinal ganglion cells, rapidly transported to the optic nerve plasma membrane and nerve terminals and metabolised. J Neurochem 61, pp. 464°473. BIOSIS Previews | EMBASE |  $Order Document

Moser, E.I., Krobert, K.A., Moser, M.B. and Morris, R.G.M., 1998. Impaired spatial learning after saturation of long-term potentiation. Science 281, pp. 2038°2041.

Mrak, R.E., Sheng, J.G. and Griffin, S.T., 1995. Glial cytokines in Alzheimer's disease. Hum Pathol 26, pp. 816°823. Abstract |  $Order Document

Mucke, L., Masliah, E., Johnson, W.B., Ruppe, M.D., Alford, M., Rockenstein, E.M., Forsspetter, S., Pietropaolo, M., Mallory, M. and Abraham, C.R., 1994. Synaptotrophic effects of human amyloid- protein precursors in the cortex of transgenic mice. Brain Res 666, pp. 151°167. Abstract |  $Order Document

Multhaup, G., 1994. Identification and regulation of the high affinity binding site of the Alzheimer's disease amyloid precursor protein (APP) to glycosaminoglycans. Biochimie 76, pp. 304°311. Abstract |  $Order Document

Multhaup, G., Bush, A.I., Pollwein, P., Masters, C.L. and Beyreuther, K., 1992. Specific binding of the Alzheimer A4 amyloid precursor to collagen, laminin and heparin. J Protein Chem 11, pp. 398°399.

Munch, G., Taneli, Y., Schraven, E., Schindler, U., Schinzel, R., Palm, D. and Riederer, P., 1994. The cognition-enhancing drug tenilsetam is an inhibitor of protein cross-linking by advanced glycosylation. J Neural Transm 8, pp. 193°208. Abstract |  $Order Document

Murayama, O., Tomita, T., Nihonmatsu, N., Murayama, M., Sun, X.Y., Honda, T., Iwatsubo, T. and Takashima, A., 1999. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett 265, pp. 61°63. SummaryPlus | Article | Journal Format-PDF (76 K)

Murayama, Y., Takeda, S., Yonezawa, K., Giambarella, U., Nishimoto, I. and Ogata, E., 1996. Cell surface receptor function of amyloid precursor protein that activates Ser/Thr kinases. Gerontology 42, pp. 2°11. Abstract |  $Order Document

Murphy, M.P., Hickman, L.J., Eckman, C.B., Uljon, S.N., Wang, R. and Golde, T.E., 1999. Gamma-secretase, evidence for multiple proteolytic activities and influence of membrane positioning of substrate on generation of amyloid beta peptides of varying length. J Biol Chem 274, pp. 11914°11923. Abstract |  $Order Document

Nakai, M., Hojo, K., Yagi, K., Saito, N., Taniguchi, T., Terashima, A., Kawamata, T., Hashimoto, T., Maeda, K., Gschwendt, M., Yamamoto, H., Miyamoto, E. and Tanaka, C., 1999. Amyloid protein (25°35) phosphoyrlates MARCKS through tyrosine kinase-activated protein kinase C signaling pathway in microglia. J Neurochem 72, pp. 1179°1186 a. Abstract |  $Order Document

Nakai, T., Yamasaki, A., Sakaguchi, M., Kosaka, K., Mihari, K., Amaya, Y. and Miura, S., 1999. Membrane topology of Alzheimer's disease-related presenilin 1. J Biol Chem 274, pp. 23647°23658 b. Abstract |  $Order Document

Nalbantoglu, J., Tirado-Santiago, G., Lahsainl, A., Poirier, J., Goncalves, O., Verge, G., Momoli, F., Weiner, S.A., Massicotte, G., Julien, J.P. and Shapiro, M.L., 1997. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387, pp. 500°505. BIOSIS Previews | EMBASE |  $Order Document

Narindrasorasak, S., Lowery, D., Gonzalez-De Whitt, P., Poorman, R.A., Greenberg, B. and Kisilevsky, R., 1991. High affinity interactions between the Alzheimer's -amyloid precursor proteins and the basement membrane form of heparan sulfate proteoglycans. J Biol Chem 266, pp. 12878°12883. BIOTECHNOBASE | EMBASE |  $Order Document

Narindrasorasak, S., Altman, R.A., GonzalezDeWhitt, P., Greenberg, B.D. and Kisilevsky, R., 1995. An interaction between basement membrane and Alzheimer amyloid precursor proteins suggests a role in the pathogenesis of Alzheimer's disease. Lab Invest 72, pp. 272°282. Abstract |  $Order Document

Narita, M., Holtzman, D.M., Schwartz, A.L. and Bu, G.J., 1997. Alpha(2)-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein. J Neurochem 69, pp. 1904°1911. Abstract |  $Order Document

Naruse, S., Thinakaran, G., Luo, J.J., Kusiak, J.W., Tomita, T., Iwatsubo, T., Qian, X., Ginty, D.D., Price, D.L., Borchelt, D.R., Wong, P.C. and Sisodia, S.S., 1998. Effect of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21, pp. 1213°1221. Abstract |  $Order Document

Nathan, B.P., Bellosta, S., Sanan, D.A., Weisgraber, K.H., Mahley, R.W. and Pitas, R.E., 1994. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264, pp. 850°852. BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document

Neve, R.L. and Kozlowski, M.R., 1995. The carboxyl-terminal 100 amino acids of the amyloid protein precursor°°role in Alzheimer's disease neurodegeneration. Dev Brain Dysfunction 8, pp. 13°24. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Neve, R.L., Boyce, F.M., McPhie, D.L., Greenan, J. and OsterGranite, M.L., 1996. Transgenic mice expressing APP-C100 in the brain. Neurobiol Aging 17, pp. 191°203. Abstract | Journal Format-PDF (1246 K)

Ninomiya, H., Roch, J.-M., Jin, L.-W. and Saitoh, T., 1994. Secreted form of amyloid /A4 protein precursor (APP) binds to two distinct APP binding sites in rat B103 neuron-like cells through two different domains, but only one site is involved in neuritotropic activity. J Neurochem 63, pp. 495°500. Abstract |  $Order Document

Nishimoto, I., Okamoto, T., Matsuura, Y., Takahashi, S., Okamoto, T., Murayama, T. and Ogata, E., 1993. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein Go. Nature 362, pp. 75°79. BIOSIS Previews | EMBASE |  $Order Document

Nitsch, R.M., Slack, B.E., Wurtman, R.J. and Growdon, J.H., 1992. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258, pp. 304°307. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Nitsch, R.M., Slack, B.E., Wurtman, R.J. and Growden, J.H., 1993. Receptor-activated and basal release of amyloid -protein precursor derivatives follow distinct mechanisms. Soc Neurosci Abstr 23, p. 355.

Nitsch, R.M., Deng, M.H., Growdon, J.H. and Wurtman, R.J., 1996. Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. J Biol Chem 271, pp. 4188°4194. Abstract |  $Order Document

Nitsch, R.M., Deng, A., Wurtman, R.J. and Growdon, J.H., 1997. Metabotropic glutamate receptor subtype mGluR1 alpha stimulates the secretion of the amyloid beta-protein precursor ectodomain. J Neurochem 69, pp. 704°712. Abstract |  $Order Document

Nitsch, R.M., Kim, C. and Growdon, J.H., 1998. Vasopressin and bradykinin regulate secretory processing of the amyloid protein precursor of Alzheimer's disease. Neurochem Res 23, pp. 807°814. Abstract |  $Order Document

Nordstedt, C., Caporoso, G.L., Thyberg, J., Gandy, S.E. and Greengard, P., 1993. Identification of the Alzheimer A4 amyloid precursor protein in clathrin-coated vesicles purified from PC12 cells. J Biol Chem 268, pp. 608°612. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Octave, J.N., de Sauvage, F. and Maloteaux, J.M., 1989. Modification of neuronal cell adhesion affects the genetic expression of the A4 amyloid peptide precursor. Brain Res 486, pp. 369°371. BIOTECHNOBASE | EMBASE |  $Order Document

Ohsawa, I., Takamura, C. and Kohsaka, S., 1997. The amino terminal region of amyloid precursor protein is responsible for neurite outgrowth in rat neocortical explant culture. Biochem Biophys Res Commun 236, pp. 59°65. Abstract |  $Order Document | CrossRef

Ohyagi, Y. and Tabira, T., 1993. Effect of growth factors and cytokines on expression of amyloid -protein precursor messenger RNAs in cultured neural cells. Mol Brain Res 18, pp. 127°132. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Okamoto, T., Takeda, S., Murayama, Y., Ogata, E. and Nishimoto, I., 1995. Ligand-dependent G protein coupling function of amyloid transmembrane precursor. J Biol Chem 270, pp. 4205°4208. Abstract |  $Order Document

OsterGranite, M.L., McPhie, D.L., Greenan, J. and Neve, R.L., 1996. Age-dependent neuronal and synaptic degeneration in mice transgenic for the C terminus of the amyloid precursor protein. J Neurosci 16, pp. 6732°6741. Abstract |  $Order Document

Oyama, F., Sawamura, N., Kobayashi, K., MorishimaKawashima, M., Kuramochi, T., Ito, M., Tomita, T., Maruyama, K., Saido, T.C., Iwatsubo, T., Capell, A., Walter, J., Grunberg, L., Ueyama, Y., Haass, C. and Ihara, Y., 1998. Mutant presenilin 2 transgenic mouse: effect on an age-dependent increase of amyloid -protein 42 in the brain. J Neurochem 71, pp. 313°322. Abstract |  $Order Document

Paganetti, P.A., Lis, M., Klafki, H.W. and Staufenbiel, M., 1996. Amyloid precursor protein truncated at any of the alpha secretase sites is not cleaved to amyloid. J Neurosci Res 46, pp. 283°293. BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document | CrossRef

Pangalos, M.N., Efthimiopoulous, S., Shioi, J. and Robakis, N.K., 1995. The chondroitin sulfate attachment site of appican is formed by splicing out exon 15 of the amyloid precursor gene. J Biol Chem 270, pp. 10388°10391 a. Abstract |  $Order Document

Pangalos, M.N., Shioi, J. and Robakis, N.K., 1995. Expression of the chondroitin sulfate proteoglycans of amyloid precursor (appican) and amyloid precursor-like protein 2. J Neurochem 65, pp. 762°769 b. Abstract |  $Order Document

Pangalos, M.N., Shioi, J., Efthimiopoulos, S., Wu, A.F. and Robakis, N.K., 1996. Characterization of appican, the chondroitin sulfate proteoglycan form of the Alzheimer amyloid precursor protein. Neurodegeneration 5, pp. 445°451. Abstract |  $Order Document

Pappolla, M.A., Sos, M., Omar, R.A., Bick, R.J., Hickson-Bick, D.L.M., Reiter, R.J., Efthimiopoulos, S. and Robakis, N.K., 1997. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neurosci 17, pp. 1683°1690. Abstract |  $Order Document

Pappolla, M., Bozner, P., Soto, C., Shao, H.Y., Robakis, N.K., Zagorski, M., Frangione, B. and Ghiso, J., 1998. Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem 273, pp. 7185°7188. Abstract |  $Order Document

Paresce, D.M., Ghosh, R.N. and Maxfield, F.R., 1996. Microglial cells internalize aggregates of the Alzheimer's-disease amyloid -protein via a scavenger receptor. Neuron 17, pp. 553°565. Abstract |  $Order Document

Paresce, D.M., Chung, H.Y. and Maxfield, F.R., 1997. Slow degradation of aggregates of the Alzheimer's disease amyloid beta-protein by microglial cells. J Biol Chem 272, pp. 29390°29397. Abstract |  $Order Document

Paris, D., Parker, T.A., Town, T., Suo, Z.M., Fang, C.H., Humphrey, J., Crawford, F. and Mullan, M., 1998. Role of peroxynitrite in the vasoactive and cytotoxic effects of Alzheimer's -amyloid(1°40) peptide. Exp Neurol 152, pp. 116°122. Abstract |  $Order Document

Parker, W.D., Parks, J., Filley, C.M. and KleinschmidtDeMasters, B.K., 1994. Electron transport chain defects in Alzheimer's disease brain. Neurology 44, pp. 1090°1096. BIOSIS Previews | Elsevier BIOBASE |  $Order Document

Parkin, E.T., Hussain, I., Turner, A.J. and Hooper, N.M., 1997. The amyloid precursor protein is not enriched in caveolae-like, detergent-insoluble membrane microdomains. J Neurochem 69, pp. 2179°2188. Abstract |  $Order Document

Pelech, S.L. and Charest, D.L., 1996. Cell cycle control in progress. In: Meijer, L., Guidet, S. and Lim-Tung, H.Y. Editors, 1996. Cell Cycle Research Plenum, New York, pp. 33°52.

Peraus, G.C., Masters, C.L. and Beyreuther, K., 1997. Late compartments of amyloid precursor protein transport in SY5Y cells are involved in beta-amyloid secretion. J Neurosci 17, pp. 7714°7724. Abstract |  $Order Document

Pereira, C., Santos, M.S. and Oliveira, C., 1998. Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. Neuroreport 9, pp. 1749°1755. Abstract |  $Order Document

Perez, R.G., Zheng, H., VanderPloeg, L.H.T. and Koo, E.H., 1997. The beta-amyloid precursor protein of Alzheimer's disease enhances neuron viability and modulates neuronal polarity. J Neurosci 17, pp. 9407°9414. Abstract |  $Order Document

Petryniak, M.A., Wurtman, R.J. and Slack, B.E., 1996. Elevated intracellular calcium concentration increases secretory processing of the amyloid precursor protein by a tyrosine phosphorylation-dependent mechanism. Biochem J 320, pp. 957°963. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Phinney, A.L., Calhoun, M.E., Wolfer, D.P., Lipp, H.P., Zheng, H. and Jucker, M., 1999. No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice. Neuroscience 90, pp. 1207°1216. SummaryPlus | Article | Journal Format-PDF (1385 K)

Pike, C.J., 1999. Estrogen modulates neuronal Bcl-x(L) expression and beta-amyloid-induced apoptosis: relevance to Alzheimer's disease. J Neurochem 72, pp. 1552°1563. Abstract |  $Order Document

Pike, C.J. and Cotman, C.W., 1995. Calretinin-immunoreactive neurons are resistant to beta amyloid toxicity in vitro. Brain Res 671, pp. 293°298. Abstract | Journal Format-PDF (772 K)

Pike, C.J., Walencewicz, A.J., Glabe, C.G. and Cotman, C.W., 1991. Aggregation-related toxicity of synthetic amyloid protein in hippocampal cultures. Eur J Pharmacol 207, pp. 367°368. EMBASE |  $Order Document

Pike, C.J., Burdick, D., Walencewicz, A.J., Glabe, C.G. and Cotman, C.W., 1993. Neurodegeneration induced by beta amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 13, pp. 1676°1687. BIOSIS Previews | EMBASE |  $Order Document

Pike, C.J., Overman, M.J. and Cotman, C.W., 1995. Amino-terminal deletions enhance aggregation of -amyloid peptides in-vitro. J Biol Chem 270, pp. 23895°23898. Abstract |  $Order Document

Pike, C.J., RamezanArab, N. and Cotman, C.W., 1997. -Amyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants. J Neurochem 69, pp. 1601°1611. Abstract |  $Order Document

Pillot, T., Goethals, M., Najib, J., Labeur, C., Lins, L., Chambaz, J., Brasseur, R., Vandekerckhove, J. and Rosseneu, M., 1999. -Amyloid peptide interacts specifically with the carboxy-terminal domain of human apolipoprotein E: relevance to Alzheimer's disease. J Neurochem 72, pp. 230°237. Abstract |  $Order Document

Ponte, P., Gonzalez-DeWhitt, P., Schilling, J., Miller, J., Hsu, D., Greenberg, B., Davis, K., Wallace, W., Lieberburg, I., Fuller, F. and Cordell, B., 1988. A new A4 amyloid mRNA contains a domain homologous to serine protease inhibitors. Nature 331, pp. 525°527. EMBASE |  $Order Document

Price, S.A., Held, B. and Pearson, H.A., 1998. Amyloid beta protein increases Ca2+ currents in rat cerebellar granule neurones. Neuroreport 9, pp. 539°545. Abstract |  $Order Document

Qiu, W.Q., Ferreira, A., Miller, C., Koo, E.H. and Selkoe, D.J., 1995. Cell-surface -amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J Neurosci 15, pp. 2157°2167. BIOSIS Previews |  $Order Document

Qiu, W.Q., Borth, W., Ye, Z., Haass, C., Teplow, D.B. and Selkoe, D.J., 1996. Degradation of amyloid beta-protein by a serine protease-alpha(2)-macroglobulin complex. J Biol Chem 271, pp. 8443°8451. BIOSIS Previews |  $Order Document

Qiu, W.Q., Ye, Z., Kholodenko, D., Seubert, P. and Selkoe, D., 1997. Degradation of amyloid protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J Biol Chem 272, pp. 6641°6646. BIOSIS Previews |  $Order Document

Querfurth, H.W., Jiang, J.W., Geiger, J.D. and Selkoe, D.J., 1997. Caffeine stimulates amyloid beta-peptide release from beta-amyloid precursor protein-transfected HEK293 cells. J Neurochem 69, pp. 1580°1591. Abstract |  $Order Document

Racchi, M., Johnston, J.A., Flood, F.M., Cowburn, R.F. and Govoni, S., 1999. Amyloid precursor protein metabolism in fibroblasts from individuals with one, two or three copies of the amyloid precursor protein (APP) gene. Biochem J 338, pp. 777°782 a. Abstract |  $Order Document

Racchi, M., Solano, D.C., Sironi, M. and Govoni, S., 1999. Activity of alpha-secretase as the common final effector of protein kinase C-dependent and -independent modulation of amyloid precursor protein metabolism. J Neurochem 72, pp. 2464°2470 b. Abstract |  $Order Document

Rankin, S. and Rozengurt, E., 1994. Platelet-derived growth factor modulation of focal adhesion kinase (P125fak) and paxillin tyrosine phosphorylation in Swiss 3T3 cells°°bell-shaped dose-response and cross-talk with bombesin. J Biol Chem 269, pp. 704°710. Abstract |  $Order Document

Raposo, G., Dunia, I., Marullo, S., Andre, C., Guillet, J.G., Strosberg, A.D., Benedetti, E.L. and Hoebeke, J., 1987. Redistribution of muscarinic acetylcholine receptors on human fibroblasts induced by regulatory ligands. Biol Cell 60, pp. 117°124.

Raposo, G., Dunia, I., Delavierklutchko, C., Kaveri, S., Strosberg, A.D. and Benedetti, E.L., 1989. Internalization of beta-adrenergic receptor in A431 cells involves non-coated vesicles. Eur J Cell Biol 50, pp. 340°352. EMBASE |  $Order Document

Ray, W.J., Yao, M., Nowotny, P., Mumm, J., Zhang, W., Wu, J.Y., Kpoan, R. and Goate, A.M., 1999. Evidence for a physical interaction between presenilin and Notch. Proc Natl Acad Sci USA 96, pp. 3263°3268. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Rhee, S.K., Quist, A.P. and Lal, R., 1998. Amyloid protein(1°42) forms calcium-permeable, Zn2+-sensitive channel. J Biol Chem 273, pp. 13379°13382. BIOSIS Previews |  $Order Document

Robner, S., Ueberham, U., Schliebs, R., Perez-Polo, J.R. and Bigl, V., 1998. The regulation of the amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling. Prog Neurobiol 56, pp. 541°569.

Roch, J.M., Masliah, E., Rochlevecq, A.C., Sundsmo, M.P., Otero, D.A.C., Veinbergs, I. and Saitoh, T., 1994. Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid A4 protein-precursor. Proc Natl Acad Sci USA 91, pp. 7450°7454. BIOSIS Previews | BIOTECHNOBASE | EMBASE | Elsevier BIOBASE |  $Order Document

Rogers, J.T., Leiter, L.M., McPhee, J., Cahill, C.M., Zhan, S.S., Potter, H. and Nilsson, L.N.G., 1999. Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences. J Biol Chem 274, pp. 6421°6431. Abstract |  $Order Document

Roher, A.E., Lowenson, J.D., Clarke, S., Woods, A.S., Cotter, R.J., Gowing, E. and Ball, M.J., 1993. -Amyloid-(1°42) is a major component of cerebrovascular amyloid deposits°°implications for the pathology of Alzheimer disease. Proc Natl Acad Sci USA 90, pp. 10836°10840. BIOSIS Previews | BIOTECHNOBASE | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Rossner, S., Ueberham, U., Schliebs, R., PerezPolo, J.R. and Bigl, V., 1998. p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells. J Neurochem 71, pp. 757°766. Abstract |  $Order Document

Rothberg, K.G., Heuser, J.E., Donzell, W.C., Ying, Y.S., Glenney, J.R. and Anderson, R.G.W., 1992. Caveolin, a protein component of caveolae membrane coats. Cell 68, pp. 673°682. BIOTECHNOBASE | EMBASE |  $Order Document

Russo, T., Faraonio, R., Minopoli, G., DeCandia, P., DeRenzis, S. and Zambrano, N., 1998. Fe65 and the protein network centered around the cytosolic domain of the Alzheimer's beta-amyloid precursor protein. FEBS Lett 434, pp. 1°7. SummaryPlus | Article | Journal Format-PDF (154 K)

Sagara, Y., Dargusch, R., Klier, F.G., Schubert, D. and Behl, C., 1996. Increased antioxidant enzyme activity in amyloid beta protein-resistant cells. J Neurosci 16, pp. 497°505. Abstract |  $Order Document

Salinero, O., Garrido, J.J. and Wandosell, F., 1998. Amyloid precursor protein proteoglycan is increased after brain damage. Biochim Biophys Acta 1406, pp. 237°250. SummaryPlus | Article | Journal Format-PDF (472 K)

Salinetti, N., Cattaneo, E., Govoni, S. and Racchi, M., 1996. Changes in amyloid precursor protein secretion associated with the proliferative status of CNS-derived progenitor cells. Neurosci Lett 212, pp. 199°203.

Sambamurti, K. and Lahiri, D.K., 1998. ERAB contains a putative noncleavable signal peptide. Biochem Biophys Res Commun 249, pp. 546°549. Abstract |  $Order Document | CrossRef

Sandbrink, R., Masters, C.L. and Beyreuther, K., 1994. Complete nucleotide and deduced amino acid sequence of rat amyloid protein precusor-like protein 2 (APLP2/APPH): two amino acids length difference to human and murine homologues. Biochim Biophys Acta 1219, pp. 167°170. Abstract |  $Order Document

Sandhu, F.A., Kim, Y., Lapan, K.A., Salim, M., Aliuddin, V. and Zain, S.B., 1996. Expression of the C terminus of the amyloid precursor protein alters growth factor responsiveness in stably transfected PC12 cells. Proc Natl Acad Sci USA 93, pp. 2180°2185. BIOSIS Previews | BIOTECHNOBASE | EMBASE | Elsevier BIOBASE |  $Order Document

Sargiacomo, M., Sudol, M., Tang, Z.L. and Lisanti, M.P., 1993. Signal-transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells. J Cell Biol 122, pp. 789°807. Abstract |  $Order Document

Sargiacomo, M., Scherer, P.E., Tang, Z.L., Kubler, E., Song, K.S., Sanders, M.C. and Lisanti, M.P., 1995. Oligomeric structure of caveolin°°implications for caveolae membrane organization. Proc Natl Acad Sci USA 92, pp. 9407°9411. BIOSIS Previews | BIOTECHNOBASE | EMBASE | Elsevier BIOBASE |  $Order Document

Schaffer, L.M., Sherin, D.S. and Brannaman, G.A., 1993. Processing of neuronally generated APP by macrophages and microglia. Exp Neurol 52, p. 296.

Schenck, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Liao, Z., Lieberburg, I., Motter, R., Mutter, L., Soriano, F., Shopp, G., Vasquez, N., Vandervert, C., Walker, S., Wogulis, M., Yednock, T., Games, D. and Seubert, P., 1999. Immunization with amyloid- attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, pp. 173°177.

Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T.D., Hardy, J., Hutton, M., Kukull, W., Larson, E., Levylahad, E., Viitanen, M., Peskind, E., Poorkaj, P., Schellenberg, G., Tanzi, R., Wasco, W., Lannfelt, L., Selkoe, D. and Younkin, S., 1996. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in-vivo by the presenilin 1 and presenilin 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 2, pp. 864°870. BIOSIS Previews | Elsevier BIOBASE |  $Order Document

Scholey, A.B., Rose, S.P.R., Zamani, M.R., Bock, E. and Schachner, M., 1993. A role for the neural cell adhesion molecule in a late, consolidating phase of glycoprotein synthesis six hours following passive avoidance training of the young chick. Neuroscience 55, pp. 499°509. BIOSIS Previews | EMBASE |  $Order Document

Schubert, D., Schroeder, R., LaCorbiere, M., Saitoh, T. and Cole, G., 1988. Amyloid protein precursor is possibly a heparan sulfate proteoglycan core protein. Science 241, pp. 223°226. EMBASE |  $Order Document

Schubert, D., Jin, L.-W., Saitoh, T. and Cole, G., 1989. The regulation of amyloid protein precursor secretion and its modulatory role in cell adhesion. Neuron 3, pp. 689°694.

Schubert, W., Prior, R., Weidemann, A., Dircksen, H., Multhaup, G., Masters, C.L. and Beyreuther, K., 1991. Localisation of Alzheimer A amyloid precursor protein at central and peripheral synaptic sites. Brain Res 563, pp. 184°194. EMBASE |  $Order Document

Schulz, J.G., Megow, D., Reszka, R., Villringer, A., Einhaupl, K.M. and Dirnagl, U., 1998. Evidence that glypican is a receptor mediating beta-amyloid neurotoxicity in PC12 cells. Eur J Neurosci 10, pp. 2085°2093. Abstract |  $Order Document

Scott, W.K., Yamaoka, L.H., Bass, M.P., Gaskell, P.C., Conneally, P.M., Small, G.W., Farrer, L.A., Auerbach, S.A., Saunders, A.M., Roses, A.D., Haines, J.L. and PericakVance, M.A., 1998. No genetic association between the LRP receptor and sporadic or late-onset familial Alzheimer disease. Neurogenetics 1, pp. 179°183.

Seabrook, G.R., Smith, D.W., Bowery, B.J., Easter, A., Reynolds, T., Fitzjohn, S.M., Morton, R.A., Zheng, H., Dawson, G.R., Sirinathsinghji, D.J.S., Davies, C.H., Collingridge, G.L. and Hill, R.G., 1999. Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38, pp. 349°359. SummaryPlus | Article | Journal Format-PDF (653 K)

Seeger, M., Nordstedt, C., Petanceska, S., Kovacs, D.M., Gouras, G.K., Hahne, S., Fraser, P., Levesque, L., Czernik, A.J., St GeorgeHyslop, P., Sisodia, S.S., Thinakaran, G., Tanzi, R.E., Greengard, P. and Gandy, S., 1997. Evidence for phosphorylation and oligomeric assembly of presenilin 1. Proc Natl Acad Sci USA 94, pp. 5090°5094. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Selkoe, D.J., 1997. Alzheimer's disease: genotypes, phenotype and treatment. Science 275, pp. 630°631. BIOSIS Previews | EMBASE |  $Order Document

Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., Sinha, S., Schlossmacher, M., Whaley, J., Swindlehurst, C., McCormack, R., Wolfert, R., Selkoe, D., Lieberburg, I. and Schenk, D., 1992. Isolation and quantification of soluble Alzheimer's peptide from biological fluids. Nature 359, pp. 325°327. EMBASE | BIOTECHNOBASE |  $Order Document

Sherrington, R., Rogaev, E.I., Liang, Y., Rogaeva, E.A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.F., Bruni, A.C., Montesi, M.P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R.J., Wasco, W., Dasilva, H.A.R., Haines, J.L., Pericakvance, M.A., Tanzi, R.E., Roses, A.D., Fraser, P.E., Rommens, J.M. and Stgeorgehyslop, P.H., 1995. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, pp. 754°760. BIOSIS Previews | BIOTECHNOBASE | EMBASE | Elsevier BIOBASE |  $Order Document

Shioi, J., Anderson, J.P., Ripellino, J.A. and Robakis, N.K., 1992. Chondroitin sulfate proteoglycan form of Alzheimer's -amyloid precursor protein. J Biol Chem 267, pp. 13819°13822. BIOTECHNOBASE | EMBASE |  $Order Document

Shioi, J., Refolo, L.M., Efthimiopoulos, S. and Robakis, N.K., 1993. Chondroitin sulfate proteoglycan form of cellular and cell-surface Alzheimer amyloid precursor. Neurosci Lett 154, pp. 121°124. BIOSIS Previews | EMBASE |  $Order Document

Shioi, J., Pangalos, M.N., Ripellino, J.A., Vassilacopoulou, D., Mytilineou, C., Margolis, R.U. and Robakis, N.K., 1995. The Alzheimer amyloid precursor proteoglycan (appican) is present in brain and is produced by astrocytes but not by neurons in primary neural cultures. J Biol Chem 270, pp. 11839°11844. Abstract |  $Order Document

Shioi, J., Pangalos, M.N., Wu, A.F. and Robakis, N.K., 1996. Structure and function of Appican, the proteoglycan form of the Alzheimer amyloid precursor. Trends Glycosci Glycotechnol 8, pp. 253°263.

Shivers, B.D., Hilbich, C., Multhaup, G., Salbaum, M., Beyreuther, K. and Seeburg, P.H., 1988. Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact. EMBO J 7, pp. 1365°1370.

Shoji, M., Golde, T.E., Ghiso, J., Cheung, T.T., Estus, S., Shaffer, L.M., Cai, X.D., McKay, D.M., Tintner, R., Frangione, B. and Younkin, S.G., 1992. Production of the Alzheimer amyloid protein by normal proteolytic processing. Science 258, pp. 126°129. BIOSIS Previews | EMBASE |  $Order Document

Simons, K. and Ikonen, E., 1997. Functional rafts in cell membranes. Nature 387, pp. 569°572. BIOSIS Previews | EMBASE |  $Order Document

Simons, M., Ikonen, E., Tienari, P.J., CidArregui, A., Monning, U., Beyreuther, K. and Dotti, C.G., 1995. Intracellular routing of human amyloid protein precursor: axonal delivery followed by transport to the dendrites. J Neurosci Res 41, pp. 121°128. BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document

Simons, M., De Strooper, B., Multhaup, G., Tienari, P.J., Dotti, C.G. and Beyreuther, K., 1996. Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons. J Neurosci 16, pp. 899°908. Abstract |  $Order Document

Simons, M., Keller, P., DeStrooper, B., Beyreuther, K., Dotti, C.G. and Simons, K., 1998. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95, pp. 6460°6464. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Sisodia, S.S. and Gallagher, M., 1998. A role for the -amyloid precursor protein in memory?. Proc Natl Acad Sci USA 95, pp. 12074°12076. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Slack, B.E., Nitsch, R.M., Livneh, E., Kunz, G.M., Breu, J., Eldar, H. and Wurtman, R.J., 1993. Regulation by phorbol esters of amyloid precursor protein release from Swiss 3T3 fibroblasts overexpressing protein kinase C-alpha. J Biol Chem 268, pp. 21097°21101. Abstract |  $Order Document

Slack, B.E., Breu, J., Petryniak, M.A., Srivastava, K. and Wurtman, R.J., 1995. Tyrosine phosphorylation-dependent stimulation of amyloid precursor protein secretion by the M3 muscarinic acetylcholine receptor. J Biol Chem 270, pp. 8337°8344. Abstract |  $Order Document

Slack, B.E., Breu, J., Muchnicki, L. and Wurtman, R.J., 1997. Rapid stimulation of amyloid precursor protein release by epidermal growth factor: role of protein kinase C. Biochem J 327, pp. 245°249. Abstract |  $Order Document

Small, D.H., Nurcombe, V., Reed, G., Clarris, H., Moir, R., Beyreuther, K. and Masters, C.L., 1994. A heparin-binding domain in the amyloid protein-precursor of Alzheimers disease is involved in the regulation of neurite outgrowth. J Neurosci 14, pp. 2117°2127. Abstract |  $Order Document

Small, D.H., Su San, M., Williamson, T.G. and Nurcombe, V., 1996. Role of proteoglycans in neural development, regeneration, and the aging brain. J Neurochem 67, pp. 889°899 a. Abstract |  $Order Document

Small, D.H., Williamson, T., Reed, G., Clarris, H., Beyreuther, K., Masters, C.L. and Nurcombe, V., 1996. The role of heparan-sulfate proteoglycans in the pathogenesis of Alzheimers-disease. Ann N Y Acad Sci 777, pp. 316°321 b. BIOSIS Previews | EMBASE |  $Order Document

Smart, E.J., Foster, D.C., Ying, Y.S., Kamen, B.A. and Anderson, R.G.W., 1994. Protein kinase C activators inhibit receptor-mediated potocytosis by preventing internalization of caveolae. J Cell Biol 124, pp. 307°313. Abstract |  $Order Document

Smith, C.J., Johnson, E.M., Osborne, P., Freeman, R.S., Neveu, I. and Brachet, P., 1993. NGF deprivation and neuronal degeneration trigger altered -amyloid precursor protein gene expression in the rat superior cervical ganglia in vivo and in vitro. Mol Brain Res 17, pp. 328°334. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Smithswintosky, V.L., Pettigrew, L.C., Craddock, S.D., Culwell, A.R., Rydel, R.E. and Mattson, M.P., 1994. Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury. J Neurochem 63, pp. 781°784. Abstract |  $Order Document

Smithswintosky, V.L., Zimmer, S., Fenton, J.W. and Mattson, M.P., 1995. Opposing actions of thrombin and protease nexin-1 on amyloid -peptide toxicity and on accumulation of peroxides and calcium in hippocampal neurons. J Neurochem 65, pp. 1415°1418. Abstract |  $Order Document

Snow, A.D., Mar, H., Nochlin, D., Sekiguchi, R.T., Kimata, K., Koike, Y. and Wight, T.N., 1990. Early accumulation of heparan sulfate in neurons and in the beta amyloid protein containing lesions of Alzheimer's disease and Down's syndrome. Am J Pathol 137, pp. 1253°1270. BIOTECHNOBASE | EMBASE |  $Order Document

Steinbach, J.P., Muller, U., Leist, M., Li, Z.W., Nicotera, P. and Aguzzi, A., 1998. Hypersensitivity to seizures in beta-amyloid precursor protein deficient mice. Cell Death Differ 5, pp. 858°866. BIOSIS Previews | EMBASE |  $Order Document

Stephenson, J., 1996. More evidence links NSAID, estrogen use with reduced Alzheimer risk. JAMA 275, pp. 1389°1390. Abstract |  $Order Document

Stix, B. and Reiser, G., 1998. -Amyloid peptide 25°35 regulates basal and hormone-stimulated Ca2+ levels in cultured rat astrocytes. Neurosci Lett 243, pp. 121°124. SummaryPlus | Article | Journal Format-PDF (130 K)

Storey, E., Beyreuther, K. and Masters, C.L., 1996. Alzheimer's disease amyloid precursor protein on the surface of cortical neurons in primary culture co-localizes with adhesion patch components. Brain Res 735, pp. 217°231. SummaryPlus | Article | Journal Format-PDF (767 K)

Storey, E., Katz, M., Brickman, Y., Beyreuther, K. and Masters, C.L., 1999. Amyloid precursor protein of Alzheimer's disease: evidence for a stable, full-length, trans-membrane pool in primary neuronal cultures. Eur J Neurosci 11, pp. 1779°1788. Abstract |  $Order Document | CrossRef

Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M.A., Enghild, J., Salvesen, G. and Roses, A.D., 1993. Apolipoprotein-E°°high avidity binding to beta amyloid and increased frequency of type-4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90, pp. 1977°1981. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Subramaniam, R., Koppal, T., Green, M., Yatin, S., Jordan, B., Drake, J. and Butterfield, D.A., 1998. The free radical antioxidant vitamin E protects cortical synaptosomal membranes from amyloid beta peptide(25°35) toxicity but not from hydroxynonenal toxicity: relevance to the free radical hypothesis of Alzheimer's disease. Neurochem Res 23, pp. 1403°1410. Abstract |  $Order Document

Suzuki, N., Cheung, T.T., Cai, X.D., Odaka, A., Otvos, L., Eckman, C., Golde, T.E. and Younkin, S.G., 1994. An increased percentage of long amyloid- protein secreted by familial amyloid- protein precursor (-APP(717)) mutants. Science 264, pp. 1336°1340. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Svensson, A.L., Alafuzoff, I. and Nordberg, A., 1992. Characterization of muscarinic receptor subtypes in Alzheimer and control brain cortices by selective muscarinic antagonists. Brain Res 596, pp. 142°148. BIOSIS Previews | EMBASE |  $Order Document

Tamaoka, A., Odaka, A., Ishibashi, Y., Usami, M., Sahara, N., Suzuki, N., Nukina, N., Mizusawa, H., Shoji, S., Kanazawa, I. and Mori, H., 1994. APP717 missense mutation affects the ratio of amyloid- protein species (A1°42/43 and A1°40) in familial Alzheimer's disease brain. J Biol Chem 269, pp. 32721°32724. Abstract |  $Order Document

Tamaoka, A., Sawamura, N., Odaka, A., Suzuki, N., Mizusawa, H., Shoji, S. and Mori, H., 1995. Amyloid protein 1°42/43 (A1°42/43) in cerebellar diffuse plaques°°enzyme linked immunosorbent assay and immunocytochemical study. Brain Res 679, pp. 151°156. Abstract | Journal Format-PDF (1143 K)

Tanaka, S., Liu, L., Kimura, J., Shiojiri, S., Takahashi, Y., Kitaguchi, N., Nakamura, S. and Ueda, K., 1992. Age-related changes in the proportion of amyloid precursor protein messenger RNAs in Alzheimer's disease and other neurological disorders. Mol Brain Res 15, pp. 303°310. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Tanaka, S., Nakamura, S., Kimura, J. and Ueda, K., 1993. Age-related change in the proportion of amyloid precursor protein messenger-RNAs in the gray matter of cerebral cortex. Neurosci Lett 163, pp. 19°21. Abstract |  $Order Document

Tang, M.X., Jacobs, D., Stern, Y., Marder, K., Schofield, P., Gurland, B., Andrews, H. and Mayeux, R., 1996. Effect of estrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 348, pp. 429°432. SummaryPlus | Article | Journal Format-PDF (75 K)

Tanzi, R.E., McClatchey, A.I., Lamperti, E.D., Gusella, J.F. and Neve, R.L., 1988. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature 331, pp. 528°530. EMBASE |  $Order Document

Tezapsidis, N., Li, H.C., Ripellino, J.A., Efthimiopoulos, S., Vassilacopoulou, D., Sambamurti, K., Toneff, T., Yasothornsrikul, S., Hook, V.Y.H. and Robakis, N.K., 1998. Release of nontransmembrane full-length Alzheimer's amyloid precursor protein from the lumenar surface of chromaffin granule membranes. Biochemistry 37, pp. 1274°1282. Abstract |  $Order Document

Thinakaran, G., Teplow, D.B., Siman, R., Greenberg, B. and Sisodia, S.S., 1996. Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells°°evidence that cleavage at the "beta-secretase" site occurs in the Golgi apparatus. J Biol Chem 271, pp. 9390°9397. Abstract |  $Order Document

Thomas, T., Thomas, G., McLendon, C., Sutton, T. and Mullan, M., 1996. Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, pp. 168°171. BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document

Tienari, P.J., De Strooper, B., Ikonen, E., Simons, M., Weidemann, A., Czech, C., Hartmann, T., Ida, N., Multhaup, G., Masters, C.L., Van Leuven, F., Beyreuther, K. and Dotti, C.G., 1996. The beta-amyloid domain is essential for axonal sorting of amyloid precursor protein. EMBO J 15, pp. 5218°5229. Abstract |  $Order Document

Tienari, P.J., Ida, N., Ikonen, E., Simons, M., Weidemann, A., Multhaup, G., Masters, C.L., Dotti, C.G. and Beyreuther, K., 1997. Intracellular and secreted Alzheimer beta-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons. Proc Natl Acad Sci USA 94, pp. 4125°4130. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Tomita, S., Kirino, Y. and Suzuki, T., 1998. Cleavage of Alzheimer's amyloid precursor protein (APP) by secretases occurs after O-glycosylation of APP in the protein secretory pathway°°identification of intracellular compartments in which APP cleavage occurs without using toxic agents that interfere with protein metabolism. J Biol Chem 273, pp. 6277°6284. Abstract |  $Order Document

Tremml, P., Lipp, H.P., Muller, U., Ricceri, L. and Wolfer, D.P., 1998. Neurobehavioral development, adult openfield exploration and swimming navigation learning in mice with a modified beta-amyloid precursor protein gene. Behav Brain Res 95, pp. 65°76. SummaryPlus | Article | Journal Format-PDF (333 K)

Turner, R.S., Suzuki, N., Chyung, A.S.C., Younkin, S.G. and Lee, V.M.Y., 1996. Amyloids beta(40) and beta(42) are generated intracellularly in cultured human neurons and their secretion increases with maturation. J Biol Chem 271, pp. 8966°8970. Abstract |  $Order Document

Ueda, K., Shinohara, S., Yagami, T., Asakura, K. and Kawasaki, K., 1997. Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals. J Neurochem 68, pp. 265°271. BIOSIS Previews | EMBASE |  $Order Document

Vassilacopoulou, D., Ripellino, J.A., Tezapsidis, N., Hook, V.Y.H. and Robakis, N.K., 1995. Full-length and truncated Alzheimer amyloid precursors in chromaffin granules: solubilisation of membrane amyloid precursor is mediated by an enzymatic mechanism. J Neurochem 64, pp. 2140°2146. Abstract |  $Order Document

Vitek, M.P., Bhattachayra, K., Glendening, J.M., Stopa, E., Vlassara, H., Bucala, R., Manogue, K. and Cerami, A., 1994. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA 91, pp. 4766°4770. BIOSIS Previews | BIOTECHNOBASE | EMBASE | Elsevier BIOBASE |  $Order Document

VonKoch, C.S., Zheng, H., Chen, H., Trumbauer, M., Thinakaran, G., VanderPloeg, L.H.T., Price, D.L. and Sisodia, S.S., 1997. Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18, pp. 661°669. SummaryPlus | Article | Journal Format-PDF (359 K)

Wallace, W.C., Akar, C.A. and Lyons, W.E., 1997. Amyloid precursor protein potentiates the neurotrophic activity of NGF. Mol Brain Res 52, pp. 201°212 a. SummaryPlus | Article | Journal Format-PDF (2697 K)

Wallace, W.C., Akar, C.A., Lyons, W.E., Kole, H.K., Egan, J.M. and Wolozin, B., 1997. Amyloid precursor protein requires the insulin signalling pathway for neurotrophic activity. Mol Brain Res 52, pp. 213°227 b. SummaryPlus | Article | Journal Format-PDF (1349 K)

Walsh, D.M., Hartley, D.M., Kusumoto, Y., Fezoui, Y., Condron, M.M., Lomakin, A., Benedek, G.B., Selkoe, D.J. and Teplow, D.B., 1999. Amyloid protein fibrillogenesis. J Biol Chem 274, pp. 25945°25952. Abstract |  $Order Document

Walter, J., Grunberg, J., Capell, A., Pesold, B., Schindzielorz, A., Citron, M., Mendla, K., St GeorgeHyslop, P., Multhaup, G., Selkol, D.J. and Haass, C., 1997. Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Proc Natl Acad Sci USA 94, pp. 5349°5354. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Wasco, W., Bupp, K., Magendantz, M., Gusella, J.F., Tanzi, R.E. and Solomon, F., 1992. Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci USA 89, pp. 10758°10762. BIOSIS Previews | EMBASE | BIOTECHNOBASE |  $Order Document

Wasco, W., Brook, J.D. and Tanzi, R.E., 1993. The amyloid precursor-like protein (APLP) gene maps to the long arm of human chromosome 19. Genomics 15, pp. 237°239. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document | CrossRef

Watanabe, T., Sukegawa, J., Sukegawa, I., Tomita, S., Iijima, K., Oguchi, S., Suzuki, T., Nairn, A.C. and Greengard, P., 1999. A 127-kDa protein (UV-DDB) binds to the cytoplasmic domain of the Alzheimer's amyloid precursor protein. J Neurochem 72, pp. 549°556. Abstract |  $Order Document

WavrantDeVrieze, F., Rudrasingham, V., Lambert, J.C., Chakraverty, S., Kehoe, P., Crook, R., Amouyel, P., Wu, W., Holmans, P., Rice, F., PerezTur, J., Frigard, B., Morris, J.C., Carty, S., Cottel, D., Tunstall, N., Lovestone, S., Petersen, R.C., ChartierHarlin, M.C., Goate, A., Owen, M.J., Williams, J. and Hardy, J., 1999. No association between the alpha-2 macroglobulin I1000V polymorphism and Alzheimer's disease. Neurosci Lett 262, pp. 137°139. SummaryPlus | Article | Journal Format-PDF (57 K)

Webster, S., Glabe, C. and Rogers, J., 1995. Multivalent binding of complement protein C1Q to the amyloid beta-peptide (A beta) promotes the nucleation phase of A beta aggregation. Biochem Biophys Res Commun 217, pp. 869°875. Abstract |  $Order Document | CrossRef

Weidemann, A., Paliga, K., Durrwang, U., Czech, C., Evin, G., Masters, C.L. and Beyreuther, K., 1997. Formation of stable complexes between two Alzheimer's disease gene products: presenilin-2 and beta-amyloid precursor protein. Nat Med 3, pp. 328°332. BIOSIS Previews | EMBASE |  $Order Document

Weiss, J.H., Pike, C.J. and Cotman, C.W., 1994. Calcium channel blockers attenuate -amyloid peptide toxicity to cortical neurons in culture. J Neurochem 62, pp. 372°375. Abstract |  $Order Document

Wernyj, R.P., Mattson, M.P. and Christakos, S., 1999. Expression of calbindin-D-28k in C6 glial cells stabilizes intracellular calcium levels and protects against apoptosis induced by calcium ionophore and amyloid beta-peptide. Mol Brain Res 64, pp. 69°79. SummaryPlus | Article | Journal Format-PDF (424 K)

White, A.R., Zheng, H., Galatis, D., Maher, F., Hesse, L., Multhaup, G., Beyreuther, K., Masters, C.L. and Cappai, R., 1998. Survival of cultured neurons from amyloid precursor protein knock-out mice against Alzheimer's amyloid toxicity and oxidative stress. J Neurosci 18, pp. 6207°6217. Abstract |  $Order Document

Whitson, J.S., Selkoe, D.J. and Cotman, C.W., 1989. Amyloid protein enhances the survival of hippocampal neurons in vitro. Science 243, pp. 1488°1490. EMBASE |  $Order Document

Williamson, T.G., Nurcombe, V., Beyreuther, K., Masters, C.L. and Small, D.H., 1995. Affinity purification of proteoglycans that bind to the amyloid protein precursor of Alzheimer's disease. J Neurochem 65, pp. 2201°2208. Abstract |  $Order Document

Williamson, T.G., Su San, M., Henry, A., Cappai, R., Lander, A.D., Nurcombe, V., Beyreuther, K., Masters, C.L. and Small, D.H., 1996. Secreted glypican binds to the amyloid precursor protein of Alzheimer's disease (APP) and inhibits APP-induced neurite outgrowth. J Biol Chem 271, pp. 31215°31221. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Wisniewski, T., Castano, E.M., Golabek, A., Vogel, T. and Frangione, B., 1994. Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro. Am J Pathol 145, pp. 1030°1035. Abstract |  $Order Document

Wolf, B.A., Wertkin, A.M., Jolly, Y.C., Yasuda, R.P., Wolfe, B.B., Konrad, R.J., Manning, D., Ravi, S., Williamson, J.R. and Lee, V.M.Y., 1995. Muscarinic regulation of Alzheimer's-disease amyloid precursor protein secretion and amyloid beta protein production in human neuronal NT2n cells. J Biol Chem 270, pp. 4916°4922. Abstract |  $Order Document

Wolfe, M.S., Xia, W., Ostaszewski, B.L., Diehl, T.S., Kimberly, W.T. and Selkoe, D.J., 1999. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and -secretase activity. Nature 398, pp. 513°517. BIOSIS Previews | Elsevier BIOBASE | EMBASE |  $Order Document

Wong, P.C., Zheng, H., Chen, H., Becher, M.W., Sirinathsinghji, D.J.S., Trumbauer, M.E., Chen, H.Y., Price, D.L., VanDer Ploeg, L.H.T. and Sissodia, S.S., 1997. Presenilin 1 is required for Notch 1 and Dll 1 expression in the paraxial mesoderm. Nature 387, pp. 288°292. BIOSIS Previews | EMBASE |  $Order Document

Woods, A.G., Cribbs, D.H., Whittemore, E.R. and Cotman, C.W., 1995. Heparan sulfate and chondroitin sulfate glycosaminoglycan attenuate beta-amyloid(25°35) induced neurodegeneration in cultured hippocampal neurons. Brain Res 697, pp. 53°62. Abstract | Journal Format-PDF (920 K)

Wu, A.F., Pangalos, M.N., Efthimiopoulos, S., Shioi, J. and Robakis, N.K., 1997. Appican expression induces morphological changes in C6 glioma cells and promotes adhesion of neural cells to the extracellular matrix. J Neurosci 17, pp. 4987°4993 a. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Wu, C.B., Butz, S., Ying, Y.S. and Anderson, R.G.W., 1997. Tyrosine kinase receptors concentrated in caveolae-like domains from neuronal plasma membrane. J Biol Chem 272, pp. 3554°3559 b. Abstract |  $Order Document

Xia, W., Zhang, J., Perez, R., Koo, E.H. and Selkoe, D.J., 1997. Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer's disease. Proc Natl Acad Sci USA 94, pp. 8208°8213. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Xu, H., Greengard, P. and Gandy, S., 1995. Regulated formation of Golgi secreted vesicles containing Alzheimer -amyloid precursor protein. J Biol Chem 270, pp. 23243°23245. Abstract |  $Order Document

Xu, H.X., Sweeney, D., Greengard, P. and Gandy, S., 1996. Metabolism of Alzheimer beta-amyloid precursor protein°°regulation by protein kinase A in intact cells and in a cell-free system. Proc Natl Acad Sci USA 93, pp. 4081°4084. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Xu, H., Sweeney, D., Wang, R., Thinakaran, G., Lo, A.C.Y., Sisodia, S.S., Greengard, P. and Gandy, S., 1997. Generation of Alzheimer amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. Proc Natl Acad Sci USA 94, pp. 3748°3752. BIOSIS Previews | BIOTECHNOBASE | EMBASE |  $Order Document

Xu, H.X., Gouras, G.K., Greenfield, J.P., Vincent, B., Naslund, J., Mazzarelli, L., Fried, G., Jovanovic, J.N., Seeger, M., Relkin, N.R., Liao, F., Checler, F., Buxbaum, J.D., Chait, B.T., Thinakaran, G., Sisodia, S.S., Wang, R., Greengard, P. and Gandy, S., 1998. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med 4, pp. 447°451. BIOSIS Previews | BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document

Yaar, M., Zhai, S., Pilch, P.F., Doyle, S.M., Eisenhauer, P.B., Fine, R.E. and Gilchrest, B.A., 1997. Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis°°a possible mechanism for Alzheimer's disease. J Clin Invest 100, pp. 2333°2340. Abstract |  $Order Document

Yamatsuji, T., Matsui, T., Okamoto, T., Komatsuzaki, K., Takeda, S., Fukumoto, H., Iwatsubo, T., Suzuki, M., Asami-Odaka, A., Ireland, S., Kinane, B., Giambarella, U. and Nishimoto, I., 1996. G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's disease-associated mutants of APP. Science 272, pp. 1349°1352 a. BIOSIS Previews | EMBASE | Elsevier BIOBASE |  $Order Document

Yamatsuji, T., Okamoto, T., Takeda, S., Murayama, Y., Tanaka, N. and Nishimoto, I., 1996. Expression of V642 APP mutant causes apoptosis as Alzheimer trait-linked phenotype. EMBO J 15, pp. 498°509 b. Abstract |  $Order Document

Yamazaki, T., Selkoe, D.J. and Koo, E.H., 1995. Trafficking of cell surface amyloid precursor protein: retrograde and transcytotic transport in cultured neurons. J Cell Biol 129, pp. 431°442. Abstract |  $Order Document

Yamazaki, T., Koo, E.H. and Selkoe, D.J., 1996. Trafficking of cell-surface amyloid beta-protein precursor. J Cell Sci 109, pp. 999°1008. Abstract |  $Order Document

Yamazaki, T., Koo, E.H. and Selkoe, D.J., 1997. Cell surface amyloid beta-protein precursor colocalizes with beta1 integrins at substrate contact sites in neural cells. J Neurosci 17, pp. 1004°1010. Abstract |  $Order Document

Yan, S.D., Chen, X., Schmidt, A.M., Brett, J., Goodman, G., Zou, Y.S., Scott, C.W., Caputo, C., Frappier, T., Smith, M.A., Perry, G., Yen, S.H. and Stern, D., 1994. Glycated tau protein in Alzheimer's disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 91, pp. 7787°7791. BIOSIS Previews | EMBASE | BIOTECHNOBASE | Elsevier BIOBASE |  $Order Document

Yan, S.D., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., Migheli, A., Naworth, P., Stern, D. and Schmidt, A.M., 1996. RAGE and amyloid -peptide neurotoxicity in Alzheimer's disease. Nature 382, pp. 685°691. BIOSIS Previews |  $Order Document

Yan, S.D., Fu, J., Soto, C., Chen, X., Zhu, H.J., AlMohanna, F., Collison, K., Zhu, A.P., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A. and Stern, D., 1997. An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease. Nature 389, pp. 689°695. BIOSIS Previews |  $Order Document

Yan, S.D., Shi, Y., Zhu, A., Fu, J., Zhu, H., Zhu, Y., Gibson, L., Stern, E., Collison, K., Al-Mohanna, F., Ogawa, S., Roher, A., Clarke, S.G. and Stern, D.M., 1999. Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in A-induced cytotoxicity. J Biol Chem 274, pp. 2145°2156. BIOSIS Previews |  $Order Document

Yang, D.S., Small, D.H., Seydel, U., Smith, J.D., Hallmayer, J., Gandy, S.E. and Martins, R.N., 1999. Apolipoprotein E promotes the binding and uptake of beta-amyloid into Chinese hamster ovary cells in an isoform-specific manner. Neuroscience 90, pp. 1217°1226. SummaryPlus | Article | Journal Format-PDF (1365 K)

Yang, Y.N., Turner, R.S. and Gaut, J.R., 1998. The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases A beta 40 and A beta 42 secretion. J Biol Chem 273, pp. 25552°25555. Abstract |  $Order Document

Yankner, B.A., Caceres, A. and Duffy, L.K., 1990. Nerve growth factor potentiates the neurotoxicity of amyloid. Proc Natl Acad Sci USA 87, pp. 9020°9023 a. BIOTECHNOBASE | EMBASE |  $Order Document

Yankner, B.A., Duffy, L.K. and Kirschner, D.A., 1990. Neurotrophic and neurotoxic effects of amyloid protein: reversed by tachykinin neuropeptides. Science 250, pp. 279°282 b. EMBASE |  $Order Document

Yatin, S.M., Aksenov, M. and Butterfield, D.A., 1999. The antioxidant vitamin E modulates amyloid beta-peptide-induced creatine kinase activity inhibition and increased protein oxidation: implications for the free radical hypothesis of Alzheimer's disease. Neurochem Res 24, pp. 427°435. Abstract |  $Order Document

Zachary, I., Sinnettsmith, J., Turner, C.E. and Rozengurt, E., 1993. Bombesin, vasopressin and endothelin rapidly stimulate tyrosine phosphorylation of the focal adhesion-associated protein paxillin in Swiss 3T3 Cells. J Biol Chem 268, pp. 22060°22065. Abstract |  $Order Document

Zambrano, N., Minopoli, G., deCandia, P. and Russo, T., 1998. The Fe65 adaptor protein interacts through its PID1 domain with the transcription factor CP2/LSF/LBP1. J Biol Chem 273, pp. 20128°20133. Abstract |  $Order Document

Zhang, Z.Y., Drzewiecki, G.J., May, P.C., Rydel, R.E., Paul, S.M. and Hyslop, P.A., 1996. Inhibition of alpha(2)-macroglobulin/proteinase-mediated degradation of amyloid beta peptide by apolipoprotein E and alpha(1)-antichymotrypsin°°evidence that the alpha(2)-macroglobulin/proteinase complex mediates degradation of the A beta peptide. Amyloid: Int J Exp Clin Invest 3, pp. 156°161. Compendex |  $Order Document

Zheng, H., Jiang, M., Trumbauer, M.E., Sirinathsinghji, D.J.S., Hopkins, R., Smith, D.W., Heavens, R.P., Dawson, G.R., Boyce, S., Conner, M.W., Stevens, K.A., Slunt, H.H., Sisodia, S.S., Chen, H.Y. and Van der Ploeg, L.H.T., 1995. -Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, pp. 525°531. Abstract |  $Order Document

Corresponding author. Tel.: +44-1382-632161; fax: +44-1382-667120.(K.C. Breen); email: k.c.breen@dundee.ac.uk

Pharmacology & Therapeutics
Journal Format-PDF (370 K)
Volume 86, Issue 2
May 2000
Pages 111-144

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