Regulation of Alzheimer L-amyloid precursor ...

Biochimica et Biophysica Acta 1502 (2000) 44^52 www.elsevier.com/locate/bba

Review

Regulation of Alzheimer L-amyloid precursor tra¤cking and metabolism1 Sam Gandy a

a;b;

*, Suzana Petanceska

a

Department of Psychiatry, The Nathan S. Kline Institute for Psychiatric Research, New York University, Orangeburg, NY 10962, USA b Fisher Center for Alzheimer Research, The Rockefeller University, New York, NY 10021, USA Received 16 June 1999; received in revised form 10 April 2000; accepted 10 April 2000

Abstract Alzheimer's disease (AD) is characterized by the intracranial accumulation of the 4 kDa amyloid-L peptide (AL), following proteolysis of a V700-amino acid, integral membrane precursor, the Alzheimer amyloid precursor protein (APP). The best evidence causally linking APP to AD has been provided by the discovery of mutations within the APP coding sequence that segregate with disease phenotypes in autosomal dominant forms of familial AD (FAD). Though FAD is rare ( 6 10% of all AD), the hallmark features (amyloid plaques, neurofibrillary tangles, synaptic and neuronal loss, neurotransmitter deficits and dementia) are indistinguishable when FAD is compared with typical, common, `non-familial', or sporadic, AD (SAD). Studies of some clinically relevant mutant APP molecules from FAD families have yielded evidence that APP mutations can lead to the enhanced generation or aggregability of AL, consistent with a pathogenic role in AD. Other genetic loci for FAD have been discovered which are distinct from the immediate regulatory and coding regions of the APP gene, indicating that defects in molecules other than APP can also specify cerebral amyloidogenesis and FAD. To date, all APP and non-APP FAD mutations can be demonstrated to have the common feature of promoting amyloidogenesis of AL. Epidemiological studies indicate that postmenopausal women on estrogen replacement therapy (ERT) have their relative risk of developing SAD diminished by about one third as compared with age-matched women not receiving ERT [M.X. Tang, D. Jacobs, Y. Stern, K. Marder, P. Schofield, B. Gurland, H. Andrews, R. Mayeux, Effect of estrogen during menopause on risk and age at onset of Alzheimer's disease, Lancet 348 (2000) 429^432]. Because of the key role of cerebral AL accumulation in initiating AD pathology, it is most attractive that estradiol might modulate SAD risk or age-at-onset by inhibiting AL accumulation. A possible mechanistic basis for such a scenario is reviewed here. ß 2000 Elsevier Science B.V. All rights reserved. Keywords: Alzheimer L-amyloid precursor; Regulation; Tra¤cking; Metabolism

1. Alzheimer's disease (AD) is associated with intracranial amyloidosis * Corresponding author. Fax: +1-914-398-5422; E-mail: [email protected] E-mail: [email protected] 1 Portions of this review have previously appeared in Trends in Endocrinology and Metabolism and are reprinted here with the permission of Elsevier Publishing.

Amyloid is a generic description applied to a heterogeneous class of tissue protein precipitates which have the common feature of a L-pleated sheet secondary structure, a characteristic which confers a¤nity for the histochemical dye Congo red. Amyloids

0925-4439 / 00 / $ ^ see front matter ß 2000 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 5 - 4 4 3 9 ( 0 0 ) 0 0 0 3 1 - 4

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S. Gandy, S. Petanceska / Biochimica et Biophysica Acta 1502 (2000) 44^52

may be deposited in a general manner throughout the body (systemic amyloids) or con¢ned to a particular organ (e.g. cerebral amyloid, renal amyloid). AD is characterized by clinical evidence of cognitive failure in association with cerebral amyloidosis, cerebral intraneuronal neuro¢brillary pathology, neuronal and synaptic loss and neurotransmitter de¢cits. The cerebral amyloid of AD is deposited around meningeal and cerebral vessels, as well as in gray matter. In gray matter, the deposits are multifocal, coalescing into miliary structures known as plaques. Parenchymal amyloid plaques are distributed in brain in a characteristic fashion, di¡erentially a¡ecting the various cerebral and cerebellar lobes and cortical laminae. The main constituent of cerebrovascular amyloid was puri¢ed and sequenced by Glenner and Wong in 1984. This 40^42 amino acid polypeptide, designated `L protein' (or, according to Masters et al., À4'; now standardized as ÀL' by The Husby Commission), is derived from a 695^770 amino acid precursor, termed the amyloid precursor protein (APP; Fig. 1), which was characterized by molecular cloning using oligonucleotide probes from the published amyloid peptide sequence. The primary citations for this molecular neuropathology review can be found elsewhere [1]. 2. AL L is a catabolite of an integral precursor The deduced amino acid sequence of APP predicts a protein with a single transmembrane domain (Fig. 1A). Isoform diversity is generated by alternative mRNA splicing and isoforms of 751 and 770 amino acids include a protease inhibitor domain (`Kunitztype protease inhibitor' domain, or KPI) in the extracellular region of the APP molecule. The ectodomains of the protease inhibitor-bearing isoforms of APP are identical to molecules previously identi¢ed according to their tight association with proteases and thus were designated `protease nexin II' (`PNII'). Identical molecules are also present in the platelet K-granules, where they were described under the name of `factor XIa inhibitor' (XIa I). Upon degranulation of the platelet, factor XIa I (PN-II/APP) exerts an antiproteolytic e¡ect on activated factor XIa at late steps of the coagulation cascade. Some evidence

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suggests that KPI-lacking isoforms may also act as regulators of proteolysis. While many bioactivities for APP have been catalogued in the literature, AL might simply be a by-product of APP metabolism which is not necessarily intimately involved with APP function. The proteolytic processing steps for APP have by now been de¢nitively identi¢ed by puri¢cation and sequencing. The ¢rst to be identi¢ed involves cleavage within the AL domain. A large amino-terminal fragment of the APP extracellular domain (PN-II; or s-APPK or APPsK , for soluble APPK is released into the medium of cultured cells and into the cerebrospinal £uid, leaving a small nonamyloidogenic carboxyterminal fragment associated with the cell. This pathway is designated the K-secretory cleavage/release processing pathway for APP, because the enzyme(s) which perform(s) this nonamyloidogenic cleavage/release has been designated K-secretase. Thus, one important processing event in the biology of APP acts to preclude amyloidogenesis by proteolyzing APP within the AL domain, between residues AL16 and AL17 (Fig. 1B). Until mid-1992, the prevailing notion was that AL production might be restricted to the brain and perhaps even then only in association with aging and AD. This concept became obsolete with the discovery by several groups that a soluble AL species (presumably a forerunner of the aggregated ¢brillar species which is deposited in senile plaque cores) is detectable in body £uids from various species and in the conditioned medium of cultured cells. Still, AL, `soluble AL' (to distinguish it from deposited AL amyloid) is not readily detectable in the lysates of most cultured cells. Soluble AL is apparently generated in several cellular compartments, including the endoplasmic reticulum, the Golgi apparatus, the trans-Golgi network and endosomes. AL production might begin by cleavage at the AL amino-terminus by another enzyme designated L-secretase (Fig. 1B), probably beginning in the constitutive secretory pathway, i.e. the trans-Golgi network (TGN). This model accounts especially well for providing a codistribution opportunity involving APP and L-secretase prior to APP's encounter with the AL-domain-destroying K-secretase which appears to act primarily at the plasma membrane. Data from one FAD mutant (the `Swedish' FAD mutant; Fig. 1B; discussed

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Fig. 1. Structure of the Alzheimer APP (A), including the ¢ne structure around the AL domain (B). The long intralumenal (or, under certain circumstances, extracellular) domain is directed leftward whilst the short cytoplasmic domain is directed rightward. FAD = familial AD.

in detail below) support this model strongly. Other data indicate that at least some AL arises from APP molecules following their residence at the cell surface; presumably these APP molecules have escaped cell-surface K-secretase and have been internalized intact, encountering L-secretase in an endosome. An AL variant bearing Glu11 at its N-terminus has been recently noted as a prominent product of APP metabolism in cultured neurons [2]. The generation and pharmacologic regulation of [Glu11 ] AL formation appears to parallel that observed for standard [Asp1 ] AL1ÿx . The cellular and biochemical origin of the alternative cleavage at Glu11 and its role in amyloidogenesis, if any, are all yet to be elucidated. It is important to appreciate that one area of particular current interest is the elucidation of the mo-

lecular and cellular mechanisms by which the carboxy-terminus of AL is generated, since this region of the APP molecule resides within an intramembranous domain (Fig. 1). The protease(s) responsible for that cleavage, designated the Q secretase(s) (Fig. 1B), are particularly interesting not only because of the novelty of the active site-substrate reaction (i.e. within a membranous domain) but also owing to evidence that another class of FAD (known as presenilin-related FAD; [3]) appears to act via control of Q secretase function [4,5]. Along this line, the AL C-terminus is heterogeneous, being composed mostly of peptides terminating at residue AL40 (Fig. 1B); however, a small but important minority of peptides terminate at residue AL42 (Fig. 1), and it is these highly aggregatable peptides which are believed to

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initiate AL accumulation in all forms of the disease [6,7]. The primary citations for the foregoing review of APP processing can also be found elsewhere [1]. 3. Pathogenic APP mutations occur within or near the AL L domain, yield APP molecules which display pro-amyloidogenic properties in vitro and Alzheimer-like phenotypes in transgenic mouse models in vivo Certain mutations associated with familial cerebral amyloidoses have been identi¢ed within or near the AL region of the coding sequence of the APP gene. These mutations segregate with the clinical phenotypes of either hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWAD, or FADDutch; Fig. 1B) or more typical familial AD (`British', Ìndiana' FAD; Fig. 1B) and provide support for the notion that aberrant APP metabolism is a key feature of AD. In FAD-Dutch, an uncharged glutamine residue is substituted for a charged glutamate residue at position 22 of AL (Fig. 1B). This mutated residue is located in the extracellular region of APP, within the AL domain, where it apparently exerts its proamyloidogenic e¡ect by generating AL molecules which bear enhanced aggregation properties and perhaps also by altering K secretase cleavage. A `Flemish' form of FAD involves a mutation at position 21 of AL (Fig. 1B) and generates a phenotype intermediate between the relatively pure vascular amyloidosis of `Dutch FAD' and the more typical FAD involving parenchymal and vascular amyloidosis. Mutations in APP which are apparently pathogenic for more typical FAD have also been discovered. In the ¢rst discovered FAD mutation, an isoleucine residue is substituted for a valine residue within the transmembrane domain, at a position two residues downstream from the carboxy-terminus of the AL domain (Fig. 1B), equivalent to ÀL44' (if such a position existed). Although a conservative substitution, the mutation segregates with FAD in pedigrees of American, European (`British') and Asian origins, arguing against the possibility that the mutations represent irrelevant polymorphisms. Other pedigrees have been discovered in which a¡ected members

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have either phenylalanyl (Ìndiana') or glycyl residues at position ÀL44'. Neuropathological examination has veri¢ed the similarity of these individuals to typical SAD neuropathology. These ÀL44' mutant APPs are the most common of the FAD-causing APP mutations and the mechanism by which the mutations exert their e¡ects appears to be by enhancing generation of hyperaggregable, C-terminally extended AL peptides (especially AL42). Another FAD pedigree has been established involving a large Swedish kindred. In this instance, tandem missense mutations occur just upstream of the amino-terminus of the AL domain. Transfection of cultured cells with APP molecules containing the `Swedish' missense mutations results in the production of six- to eight-fold excess soluble AL above that generated from wild-type APP. An important issue for clari¢cation in sporadic AD will be to establish whether hyperaggregation or hyperproduction of AL (or neither) is/are important predisposing factor(s) to this much more commonly encountered clinical entity. The primary citations for the foregoing review of the genetic-neuropathological correlations of APP mutant FAD can be found elsewhere [1]. Some of the most exciting and newest evidence in support of the pathogenicity of these mutants has arisen from the recent demonstration that certain mutant APP transgenic mice exhibit not only cerebral amyloidosis but also neuro¢brillary tangle epitopes and neuronal loss [8]. If these animals also meet key behavioral criteria, Koch's postulates will have been met for the re-creation of all key features of AD in a species not otherwise susceptible to the illness. 4. Signal transduction regulates the relative utilization of APP processing pathways in cultured cell lines, in primary neurons and in rodents in vivo As work continues toward molecular discovery of K-, L- and Q- secretase enzymes, substantial progress has been made toward understanding the regulation of APP cleavage. For example, the relative utilization of the various alternative APP processing pathways appears to be at least partially cell-type determined, with transfected AtT20 cells secreting virtually all APP molecules whereas cell lines of astrocytic origin

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release little or no soluble APP. In neuronal-like cells, the state of di¡erentiation plays a role in determining the relative utilization of the pathways, with the di¡erentiated neuronal phenotype being associated with relatively diminished basal utilization of the nonamyloidogenic K-secretase cleavage/release pathway. It is also well-accepted that certain signal transduction systems involving protein phosphorylation are important regulators of APP cleavage, acting in many cases by stimulating the relative activity of nonamyloidogenic cleavage by K-secretase. The role of protein kinase C (PKC) and PKC-linked ¢rst messengers has received the most attention. In many types of cultured cells, activation of PKC by phorbol esters dramatically stimulates APP proteolysis [9] and sAPPK cleavage/release [10^12]. PKC-stimulated K-secretory cleavage of APP may also be induced by the application of neurotransmitters and other ¢rst messenger compounds whose receptors are linked to PKC [13,14]. Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, also increases APP proteolysis and release via the K-secretase pathway [13,14]. Indeed, it has recently been shown in primary neuronal cultures that protein phosphatase inhibition by okadaic acid is much more e¡ective in lowering AL production than is PKC activation [2]. Thus, either stimulation of PKC or inhibition of protein phosphatases 1 and 2A is su¤cient to produce a dramatic acceleration of nonamyloidogenic APP degradation (not shown). PKC-activated APP processing can be demonstrated to diminish the generation of AL in virtually every situation tested to date, including primary neuronal cultures and rodent brain in vivo [15^ 17]. This phenomenon is sometimes referred to as `regulated cleavage of APP' or `reciprocal regulation of APP metabolism'; i.e. when certain signals are activated, K secretase cleavage increases and L and Glu11 -secretase cleavages decrease [2]. Steroid hormones such as 17L-estradiol [18^20] and dihydroepiandrostenedione (DHEA; [21]) are other signal transduction compounds which can apparently regulate APP metabolism in vitro. Several of these investigators [19,20] have demonstrated that estradiol diminishes AL generation, while others [18,21] have documented accumulation of sAPPK in the conditioned media of cultured cells treated with estradiol [18] or DHEA [21]. One attractive explan-

ation for the accumulation of sAPP is that gonadal steroids might stimulate either the amount or the activity of K-secretase. This explanation is consistent with the ¢nding that the cell-associated product of this activity (the 9-kDa nonamyloidogenic carboxyterminal fragment) is increased by estrogen treatment [18]. For estradiol in particular, one means by which the activity of K-secretase might increase is by an increase in the level or activity of PKC, leading to increased `regulated APP cleavage' along the pathway outlined above. Estrogen has been shown to regulate PKC in both normal and neoplastic tissue and to potentiate the phorbol ester-stimulated release of luteinizing hormone from cultured pituitary cells. The e¡ects of estrogen on PKC might be mediated by polypeptide growth factors, many of which activate PKC and a number of which have been demonstrated to enhance the accumulation of sAPPK in the conditioned media of cultured cells. The colocalization of estrogen receptors in the basal forebrain, cerebral cortex and hippocampus with the receptors for nerve growth factor, as well as with nerve growth factor itself, is consistent with the idea that growth factors might play a role in mediating the e¡ects of estrogen in the central nervous system. A review of the literature associating estradiol with protein kinase may be found elsewhere [18]. Extending this line of reasoning, a more complex relationship involving intercellular signals and APP metabolism is currently evolving: both steroid hormones and neurotrophins have been demonstrated to potentiate the ability of incoming neurotransmitters to activate the `regulated cleavage of APP', as measured by sAPPK release [22^26]. The `regulated cleavage' model makes it likely that when compounds from either or both of these classes of substances (i.e. gonadal steroids, neurotrophins) are present at the time of neurotransmitter application, the fold-diminution of AL and [Glu11 ] AL will be greatly enhanced. Assessment of this model is currently underway. 5. Insights into mechanism(s) of regulated APP processing In general terms, the possible mechanisms for activated processing of integral molecules can be con-

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ceptualized as involving either activation or redistribution of either the substrate (i.e. APP) or the enzyme (i.e. K-secretase). Based on APP cytoplasmic tail mutational analyses [27,28], the `substrate activation' model [29] is inadequate to explain activated processing of APP, since abrogation of APP cytoplasmic tail phosphorylation fails to abolish PKC-regulated Kcleavage. In order to test the model of PKC-regulated APP redistribution, Xu et al. demonstrated that the PKC-stimulated biogenesis of nascent transport vesicles from the trans-Golgi network includes vesicles which bear [35 SO4 ]APP [30]. These vesicles would be predicted to fuse with the plasma membrane where codistribution of APP and K-secretase would take place, leading to generation of sAPPK at the plasma membrane and release of that sAPPK into the culture medium. Given the preponderant localization of APP within the TGN [31], it is likely that PKC-regulated TGN vesicle biogenesis plays a role in regulating APP metabolism, although its importance cannot be completely assessed until the identi¢cation of all relevant PKC targets of this apparatus has been completed. Along a related line of investigation, Bosenberg et al. [32] succeeded in demonstrating faithful activated processing of the TGF-K precursor in porated cells in the virtual absence of cytosol and in the presence of N-ethylmaleimide or 2.5 M NaCl. The preservation of activated processing under such conditions suggests that extensive vesicular tra¤cking is unlikely to be required for all forms of activated processing and supports a model of direct or indirect enzyme activation which involves an intrinsic plasma membrane mechanism (e.g. direct phosphorylation of an K-secretase or its regulatory subunit). Cell biological and molecular cloning data indicate that APP K-secretases include, or are related to, the metalloproteinase family of adamlysins, including TGFK and protumor necrosis factor convertases. These enzymes appear to have overlapping speci¢cities for these substrates. Several candidate secretases have recently been successfully cloned and these data should facilitate the resolution of the issue of which enzymes are most important for cleaving which substrates. [33^ 36] Aspartyl proteinases are the most important Ksecretases in yeast [36], and their potential roles, if any, in mammalian APP metabolism, remain to be elucidated.

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6. Therapeutic manipulation of AL L generation via ligand or hormonal manipulation From a therapeutic standpoint, then, the modulation of APP metabolism via signal transduction pharmacology might be bene¢cial in individuals with, or at risk for, AD (reviewed in [1,12,17,37]) and it is along this line that 17L-estradiol, via its possible ability to elevate PKC activity (reviewed in [18]), came to be identi¢ed as a potential modulator of AL metabolism. This phenomenon is now under investigation in living animals. The ability of estrogen to modulate AL metabolism in vivo was recently tested in two animal systems: guinea pigs and plaque forming mice (Du¡ and Refolo, personal communication; Petanceska, Nagy, Frail and Gandy, submitted for publication). Prolonged ovariectomy of guinea pigs was associated with a pronounced increase in brain AL levels as compared to intact animals. This ovariectomy-induced increase was signi¢cantly reduced in guinea pigs receiving 17L-estradiol. Similarly, ovariectomy of transgenic, plaque forming mice at an age when AL deposition is incipient resulted in enhanced brain amyloidosis. The contributions of altered AL generation and altered AL clearance to the observed changes in brain AL levels remain to be determined. Further studies are also needed to elucidate whether the observed e¡ects on AL metabolism occur in response to activation of brain estrogen receptors or whether they are mediated by estrogen receptor-independent mechanisms. However, these two studies strongly infer that cessation of ovarian estrogen production in post-menopausal women might facilitate AL deposition by increasing the local concentrations of AL peptides in brain and that the negative correlation between hormone replacement therapy of post-menopausal women and AD is at least in part due to the AL-lowering e¡ect of estrogen. Estradiol might also modify other factors contributing to AL deposition and ¢bril formation, including the processing of soluble AL into an aggregated form and/or the association of AL with other molecules, such as K-1-antichymotrypsin, heparan sulfate proteoglycan and apolipoprotein E [38]. In particular, it has recently been recognized that apolipoprotein E is an important participant in AL accumulation [39] and that apolipoprotein E isoforms play

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important roles as di¡erential determinants of risk for AD [40]. Human postmortem [41] and cell culture [42] data are also beginning to indicate that apolipoprotein E isoforms exert at least some of their e¡ects via controlling AL accumulation, perhaps at the stage of clearance of AL peptides. Apolipoprotein E-isoform-speci¢c synaptic remodelling also appears to be a consistent and potentially relevant observation [43]. Events beyond AL deposition may also be crucial in determining the eventual toxicity of AL plaques. Aggregation of AL is important for in vitro models of neurotoxicity, but the relevance of this phenomenon for the pathogenesis of AD is unclear, since AL deposits may occur in normal aging, in the absence of any evident proximate neuronal injury [44]. This suggests that other events must distinguish `di¡use' cerebral amyloidosis with wispy deposits of AL alone from `full-blown' AD with neuritic plaques, and neuron and synapse loss. One intriguing possible contributing factor is the association of complement components with AL. In cerebellum, where AL deposits appear to cause no injury, plaques are apparently free of associated complement, while in the forebrain, complement associates with plaques, perhaps becoming activated and injuring the surrounding cells [45]. Other, as-yet undiscovered plaque-associated molecules may also play important roles. It should also be possible to apply animal models of AL deposition and neurodegeneration [8] to begin to elucidate whether the e¡ect of estrogen to delay or prevent AD in postmenopausal women is due to one or a combination of its various documented activities relevant to the pathogenesis of AD, i.e. lowering AL load, sustaining the basal forebrain cholinergic system [46], modulating interactions with growth factors and/or their receptors [47], supporting neuritic plasticity [48] or serving as an antioxidant [49]. One cannot yet exclude the possibility that estradiol plays several of these roles in its apparent2 ability to delay and/or prevent AD [50,51]. Acknowledgements This work was supported by the USPHS, the New York State O¤ce of Mental Health and the Research Foundation for Mental Hygiene. S.G. receives or has

received honoraria and/or extramural support from the Women's Health Research Institute of WyethAyerst Pharmaceuticals (a division of American Home Corporation), Warner Lambert/Parke-Davis Pharmaceuticals, Ho¡man La Roche Pharmaceuticals and Neurogen Corporation.

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