|1 of 5|
|Pharmacology & Therapeutics|
|Volume 86, Issue 2||SummaryPlus|
|Pages 111-144||Journal Format-PDF (370 K)|
Copyright (c) 2000 Elsevier Science Inc. All rights reserved.
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.
Christine M. Coughlana and Kieran C. Breen, , b
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
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
Protein kinase C 121
Muscarinic receptors 122
Growth factors 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
Apolipoprotein E 128
The inflammatory response 128
The C100 protein 129
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
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.
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.
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.
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.
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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
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
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