The amyloid precursor protein and its network of interacting proteins: physiological and pathological implications

Brain Research Reviews 48 (2005) 257 – 264 www.elsevier.com/locate/brainresrev

Review

The amyloid precursor protein and its network of interacting proteins: physiological and pathological implications Claudio Russoa,*, Valentina Veneziaa, Emanuela Repettoa, Mario Nizzaria, Elisabetta Violanib, Pia Carloa, Gennaro Schettinia,* a

Section of Pharmacology and Neuroscience, Department of Oncology, Biology and Genetics, University of Genova, Largo R. Benzi 10, 16132 Genova, Italy b Neuropharmacology Section, OASI Institute for Research and Care (IRCCS) on Mental Retardation and Brain Aging, 94018 Troina (EN), Italy Accepted 9 December 2004

Abstract The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the pathogenesis of Alzheimer’s disease that generates h-amyloid peptides and causes plaque formation. APP and some of its C-terminal proteolytic fragments (CTFs) have also been shown to be in the center of a complex protein–protein network, where selective phosphorylation of APP C-terminus may regulate the interaction with cytosolic phosphotyrosine binding (PTB) domain or Src homology 2 (SH2) domain containing proteins involved in cell signaling. We have recently described an interaction between tyrosine-phosphorylated CTFs and ShcA adaptor protein which is highly enhanced in AD brain, and a new interaction between APP and the adaptor protein Grb2 both in human brain and in neuroblastoma cultured cells. These data suggest a possible role in cell signaling for APP and its CTFs, in a manner similar to that previously reported for other receptors, through a tightly regulated coupling with intracellular adaptors to control the signaling of the cell. In this review, we discuss the significance of these novel findings for AD development. D 2004 Published by Elsevier B.V. Theme: Disorders of the nervous system Topic: Degenerative disease: Alzheimer’s—miscellaneous Keywords: Alzheimer’s disease; Signal transduction; ShcA; Neurodegeneration

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APP and its C-terminal domain . . . . . . . . . . . . . . . . . . . . . . 2.1. The C-terminal fragments (CTFs). . . . . . . . . . . . . . . . . . 2.2. The phosphorylation of the APP C-terminus and the cell signaling Shc and Grb2 adaptors . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. ShcA and Grb2 in AD brain . . . . . . . . . . . . . . . . . . . . 3.2. ShcA and APP signaling: PTB and SH2 domains . . . . . . . . . 3.3. Grb2 and APP signaling: PTB and SH2 domains . . . . . . . . .

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* Corresponding authors. Department of Oncology, Biology and Genetics University of Genova, Largo R. Benzi 10, 16132 Genova, Italy. Fax: +39 010 5737257. E-mail addresses: [email protected] (C. Russo)8 [email protected] (G. Schettini). 0165-0173/$ - see front matter D 2004 Published by Elsevier B.V. doi:10.1016/j.brainresrev.2004.12.016

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4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

2. APP and its C-terminal domain

Alzheimer’s disease is a heterogeneous neurodegenerative disorder with insidious onset and irreversible progression. The prognosis of the disease is an inexorable decline of cognitive functions, and to date, there are no effective therapies [20,50]. Clinically, it is characterized by loss of memory, followed by a progressive deterioration of all the mental functions and pathologically by the progressive neuronal degeneration of both cerebral and limbic cortices, reactive gliosis, and deposition in the brain parenchyma of amyloid aggregates (or plaques) closely associated with dystrophic neurons. Histopathologically, there are activated phagocytic microglia and intraneuronal aggregates of disrupted microtubuli, known as bneurofibrillary tanglesQ. Alzheimer’s disease is genetically linked to a few molecules, one of which is the amyloid precursor protein (APP), a type I transmembrane protein that undergoes enzymatic processing to produce various fragments [15,23,50]. Numerous experimental results indicate that APP plays a crucial role in the pathogenesis of Alzheimer’s disease. In fact, the main constituent of senile plaques, the beta-amyloid peptide (Ah), derives from the processing of APP, and mutations of the APP gene are responsible for rare cases of familial Alzheimer’s disease [15,20,50]. Furthermore, presenilins, which are part of the molecular machinery that processes APP, when mutated are responsible for most of the cases of familial Alzheimer’s disease. More than 70 different mutations in presenilin 1 (PS1) have been associated with inherited early onset Alzheimer’s disease [18,30,44,45]. The parenchymal deposition of heavily aggregated amyloid peptides in the brain of Alzheimer’s disease patients is thought to be a central event in the Alzheimer’s disease pathogenesis and the so-called bamyloid hypothesisQ links plaque formation, neurodegeneration, and Alzheimer’s disease pathology with the abnormally enhanced formation of such amyloid peptides in the brain [20,23,50]. Recently, different findings suggest that the short cytodomain of APP plays a key role in the regulation of these events. In fact, this cytodomain contains a YENPTY motif that interacts with several adaptor proteins [12,15]. Unfortunately, the pathophysiological significance and the putative role in cell signaling or in amyloid formation for many of these interactions are not yet understood. This review will focus on discussing the potential significance of selective phosphorylation of APP for the induction of different cellular pathways. This has implications for understanding both the normal biological functions of APP and its pathological role in the formation of Ah peptides and the genesis of Alzheimer’s disease.

2.1. The C-terminal fragments (CTFs)

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The pathological cascade which leads to clinical manifestations of Alzheimer’s disease has not been fully characterized although the bamyloid hypothesisQ has been used to explain certain aspects of Alzheimer’s disease pathology. According to this hypothesis, the accumulation of Ah is the primary event that leads to all subsequent events in the pathology of Alzheimer’s disease [20,50]. It is well demonstrated that APP is first cleaved by two different proteolytic enzymes, named a- and h-secretases [1,56,57]. These cleavages generate soluble extracellular fragments, named a- and h-APPs, and at least three forms of transmembrane stubs or CTFs: C83 (as a consequence of the activity of a-secretase), C89, and C99 (generated by h-secretase) [34,44,53]. These stubs are then substrates of a third enzyme, the g-secretase, which cleaves them within the transmembrane helix, generating heterogeneous Ah fragments [23,43,45]. The cleavage of C83, C89, and C99 by g-secretase also results in the generation of C-terminal peptides of 57–58 residues (APP intracellular domain, AICD) [38]. This cleavage is not as specific as once thought, and g and e cleavages are now described to justify the presence of multiple fragments (Fig. 1). APP is also a substrate of caspases that cleave its cytosolic domain 31 residues upstream from the C terminus [4]. Whereas hsecretase has been identified as the membrane-bound aspartyl protease BACE (h site APP cleaving enzyme), the identity of g-secretase has remained elusive. Recent evidence suggests that g-secretase is a large protein complex in which presenilin likely possesses a catalytic activity with other potential regulatory proteins such as Nicastrin, APH, and Pen1 [14,21]. Recent evidence suggests that BACE1 activity may be enhanced in Alzheimer’s disease brain, likely contributing to increased h-amyloid formation and certainly enhancing the formation of C99 and C89 which represent the main products of its activity [17,62]. The C99 polypeptide accumulates in significant quantity in neurons expressing mutant APP and its expression in vivo can lead to cognitive dysfunction in animal models [6,34,37]. However, the mechanisms that underlie CTFs neurotoxicity are still unknown. An increased formation of CTFs in plaque-free Down syndrome cases, years before the formation of plaques and presence of neurodegeneration, is in agreement with the hypothesis that accumulation of C99 is involved in Alzheimer’s disease neurodegeneration [43]. In addition, presenilins are complexed with the g-secretase substrates

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Fig. 1. Schematic representation of the progressive cleavage of APP by a, h, and g secretases. Here are represented the fragments generated by the proteolytic activity of the different secretases to form amyloid h-peptides and the various C-terminal fragments. Also depicted is a caspase site that forms a short (31 amino acids) C-terminal fragment.

C83 and C99 in intracellular compartments [61], and this interaction suggests an influence on the enzyme that generates CTFs: i.e., on h-secretase activity [18,42]. The shorter CTFs, such as AICD, are thought to be involved in yet unclear neurodegenerative processes. It has been found that AICD is able to trigger apoptosis or lower the threshold of the cell to other apoptotic stimuli to regulate Ca2+ release and possibly transcription upon nuclear translocation. Additionally, the proteolytic processing of APP recalls that of another membrane protein, named Notch, whose presenilin-dependent cleavage generates a nuclear-targeted fragment exactly as it occurs for APP [21,51,51]. In fact, a complex containing AICD, the adaptor protein Fe65, and the histone acetyl transferase Tip60 are able to activate the transcription of a reporter gene [9]. Therefore, it has been hypothesized that the cleavage of APP by h- and/or g-secretases and the resulting cleavage of C83, C89, or C99 by g-secretase result in the release of AICD from the membrane anchor and in its translocation into the nucleus, where, in association with other proteins, it could regulate gene transcription [2,9,28,65]. 2.2. The phosphorylation of the APP C-terminus and the cell signaling As described above, while the functions of the APP ectodomain remain elusive, its cytodomain is the center of a complex network of interactions with several adaptor proteins. The cytoplasmic tail of APP undergoes posttranslational modification events such as threonine (Thr) and tyrosine (Tyr) phosphorylation [3,25,55,67]. In differentiated PC12 cells and in SH-SY5Y cells, APP Thr 668

(numbering for the APP 695 isoform) phosphorylation is mediated by Cdk5 [25]. Glycogen synthase-3 and more efficiently c-Jun N-terminal kinase-3 also phosphorylate Thr 668 in vitro [26]. Phosphorylation of Tyr 682 can be mediated by a constitutively active form of the tyrosine kinase Abl [66] or by overexpression of the nerve growth factor receptor tyrosine-kinase receptors A (TrkA) [54]. Recently, Src kinase has been involved as well in the activation of this residue [67]. These phosphorylation events are detected in the brains of normal subjects as well as in patients with Alzheimer’s disease. The YENPTY motif, historically described as internalization motif present in the C-terminal domain of APP, is now considered central in the regulation of intracellular events regarding APP activity. This motif is peculiar of several tyrosine-kinase receptors (TKR) and of non-receptor tyrosine kinase (TK). In particular, in TKR, the tyrosine residue of this motif is phosphorylated upon TK activation and the NPXpY motif functions as a docking site for the phosphotyrosine-binding domain (PTB) present in several adaptor proteins interacting with TKR and non-receptor-TK [49]. Some of them bind to the YENPTY APP motif lying between amino acids 682 and 687 (using APP 695 numbering). In particular, APP (or its CTFs) can interact with X11 [7], Fe65 [7,16], mDab [24], c-Abl [66], Shc [44,55], JIP-1 [48], Numb [40], and with Grb2 [59,67]. It is worth noting that X11 stabilizes APP, preventing its cleavage by h- and g-secretases, whereas Fe65 might regulate Ah formation, cell movement, and even the transcriptional activity of APP C-terminus [3,8,9,46]. These observations suggest that some of the protein–protein interactions may have a role in the amyloidogenic pathway.

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3. Shc and Grb2 adaptors 3.1. ShcA and Grb2 in AD brain Among all these interacting proteins, apparently only ShcA and Grb2 require the specific tyrosine phosphorylation of Tyr 682 of APP [55,67] and the amounts of ShcA and CTFs/ShcA/Grb2 complexes are significantly increased in AD brain as compared to control [44], thus suggesting a pathogenic correlation. These data show that a subset of CTFs interacts with Shc and Grb2 proteins, suggesting that APP through its cleaved forms might transduce an intracellular signal through SH2 and PTB interacting adaptors [44]. The effect of such interaction is likely linked to the activation of the MAPK pathway, as shown in AD brain and in thrombin-treated astrocytes as well [44]. The enhanced level of ShcA protein in Alzheimer’s patients, the peculiar staining of activated astrocytes around amyloid plaques, and the increased CTFs–ShcA interaction in Alzheimer’s disease subjects altogether suggest that the activation of this pathway may play a role in Alzheimer’s disease. A consequence is that the phosphorylation of CTFs might be a very tightly regulated process, in which the kinase(s) involved may have a significant role not only for the underlying signaling, but also for the activation or inhibition of the amyloidogenic pathway. Recent data in fact suggest that Abl and Src kinases may be the kinases responsible for the activation of the APP C-terminus [19,66]. It is still unclear whether the Tyr phosphorylation of APP and of a CTF subset, the binding with ShcA and/or Grb2 adaptors, and the formation of amyloid-h are mutually exclusive or correlated events. Considering that the family of Shc adaptors and Grb2 do usually connect growth factor receptors to specific signaling pathways (typically Ras/ MAPK but also PI3K) and are involved in oncogenic proliferation, neuronal development, cell differentiation, and apoptosis [10,13,36,47,63], we can hypothesize that posttranslational modifications such as a selective phosphorylation or de-phosphorylation of APP or of its CTFs might couple them to different cellular pathways. Understanding these pathways is important for elucidating normal biological functions of APP, as well as its pathological role in the genesis of Alzheimer’s disease. 3.2. ShcA and APP signaling: PTB and SH2 domains Among the different APP-interacting proteins, there is a class of cytoplasmic proteins containing a phosphotyrosinebinding (PTB) domain such as Fe65, X11, JIP1, JIP2, mDab1, Numb. The PTB domain of these proteins interacts in a phosphorylation-independent manner with the YENPTY sequence present in the intracellular domain of APP. We have found that phosphorylation of Tyr 682 affects the interaction of APP with some binding partners [44,66]. ShcA and -C, members of a family of cytoplasmic adaptor proteins that also includes ShcB, contain a PTB region that

binds to the YENPTY APP motif [10,49]. However, unlike the other PTB-containing proteins that interact with APP, ShcA and -C seem to associate with APP only when Tyr 682 is phosphorylated (Fig. 2). Interestingly, the expression level of ShcA protein is augmented in Alzheimer’s disease brains as compared with normal, non-demented brains [44]. These data underscore the biological relevance of APP phosphorylation. Moreover, they suggest that these phosphorylation events may control APP functions by regulating the affinity of APP for distinct binding partners. The fact that thrombin may trigger the CTFs–ShcA interaction [44] suggests that the signaling activity through CTFs is tightly regulated and that a cascade of events involving kinase(s) activation, APP/ CTFs phosphorylation, and Shc interaction is required. The increased ERK1,2 phosphorylation described in Alzheimer’s disease brain and in thrombin-activated astrocytes [44] suggests that ShcA activation is likely responsible for the induction of a glial-associated mitogenic pathway (Fig. 2). ShcC, which is co-precipitated with CTFs in human brain, as reported [10], is expressed at very low levels or virtually absent in cultured proliferating astrocytes. In the human adult brain, it is likely produced in neurons or in meningeal vessels with no significant differences between Alzheimer’s disease and control subjects [44]. The adapter protein Shc is a regulator of downstream signaling events that lead to diverse biological processes and it can play its role through the activation of Ras protein by a variety of receptors, such as growth factor receptors, G protein-coupled receptors, and cytokine receptors [10,31,49]. The Shc gene encodes overlapping proteins of 46, 52, and 66 kDa (p46, p52, and p66), which share common structural characteristic [35,60]. All contain one Src homology 2 (SH2) domain, thought to direct their interaction with phosphotyrosine-containing proteins, and a region rich in glycine and proline residues with homology to the a1-chain of collagen (CH) domain [10]. An additional domain in the N-terminal region of Shc has also been identified which binds to tyrosine phosphorylated proteins through a phosphotyrosine-binding domain (PTB) [10,49]. 3.3. Grb2 and APP signaling: PTB and SH2 domains The Shc receptor interaction can be mediated via either the SH2 or the PTB domain. Following activation of many receptors, Shc is tyrosine phosphorylated on Y317 and subsequently interacts with the growth factor receptor-bound protein 2 (Grb2). Grb2, in turn, binds to a Ras guanine nucleotide exchange factor mSOS and catalyzes the exchange of GDP for GTP on Ras. The Shc–Grb2–mSOS complex becomes localized to the membrane through the interaction of Shc with the activated, tyrosine-phosphorylated receptor, thereby leading to Ras activation [10,49]. In a recent study, we have described a new APP interacting protein Grb2 [58,59,67]. Grb2 directly interacts with APP and for its interaction requires as well the phosphorylation of Tyr 682 of APP [67]. Unlike other interacting proteins that

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Fig. 2. APP is a transmembrane phosphoprotein whose progressive cleavage is regulated by BACE1 and by g-secretase complex. The g-secretase activity is presenilin-dependent. The C-terminus of APP comprises a peculiar motif (the YENPTY) that is conserved in the holoprotein as well as in the multiple fragments generated upon activation of a, h, and g secretases and even upon caspase’s cleavage. The YENPTY motif represents a docking site for multiple interacting proteins. Among others, ShcA and Grb2 apparently compete for the same phosphorylation site (tyrosine 682) and may transduce an intracellular signal, likely linked to p44/42ERK, in a coordinate fashion. Alternatively, Grb2 may interact directly with APP, without the cooperation of ShcA to transduce a yet unclear signal.

bind the YENPTY motif via their PTB domain, Grb2 binds to YENPTYvia its SH2 region [67]. Indeed, a complex of Grb2APP is detectable in human brains and its amount is apparently increased in Alzheimer’s disease brains. In proliferating neuroblastoma SH-SY5Y cells, APP695 interacts with Grb2 adaptor without the involvement of ShcA. In apoptotic conditions, we observed the downregulation of the complex between APP and Grb2, the contemporary formation of a new complex involving tyr-phosphorylated CTFs, ShcA and Grb2, and a parallel long-term activation of p44/42 ERK [59]. Altogether, these data suggest that Grb2 may mediate some biological and perhaps pathological APP/ CTF-related function independently of ShcA (Fig. 2). The physical association of endogenous APP and Grb2 in the adult human brain and the augmentation in APP– Grb2 complexes in Alzheimer’s disease patients underscore the biological and/or pathological relevance of these findings and prompt us to speculate about the possible functional consequences of this interaction. The Grb2 involvement in the activation of the (MAPK) pathways cascade is well known [10,13,27,39,41]. Considering that the phosphorylation of p42/p44 ERK is increased in Alzheimer’s disease brains [44], is modulated in vitro upon apoptotic induction by CTFs [59], and that activated MAPKs can participate in the abnormal hyper-phosphorylation of tau in Alzheimer’s disease [22,23], the interaction between Grb2 and APP/CTFs has the potential role to link APP to MAPK activation and possibly to tau hyper-

phosphorylation (Fig. 2). It is worth noting that besides its involvement in signal transduction pathways mediated by tyrosine kinase receptors, Grb2 may also anchor to a number of proteins involved in cell signaling and vesicular trafficking, such as dynamin and synapsin [33,64], or to proteins regulating cytoskeletal dynamics, cell cycle, and metastatic proliferation [5,11,13,27,29,32,39,47,52]. At present, it is unclear whether APP may have a role in some of these cell activities through its interaction with Grb2.

4. Conclusions Many receptors require phosphorylation in tyrosine in order to be activated and transfer a physiological signal into the cell. The receptor-like structure of APP has been previously linked to Go protein transduction mechanism, although not exhaustively, but the physiological function of APP is still unclear. A second theory, complementary to the amyloid hypothesis, proposes APP as a cell surface receptor and suggests that the disruption of the normal signaling function of APP can cause neuronal death, Ah formation, and eventually Alzheimer’s disease. Since the cytoplasmic domain of APP is anchored to a complex protein network that might function in neuronal cell migration, axonal elongation, and dendritic arborization, the proteolysis of APP might be critically involved in intracellular signaling events. It is still unclear whether

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these multiple protein–protein interactions, in which APP has a central role, have functional significance for Alzheimer’s disease generation. Apparently, the interaction between the APP C-terminus and FE65 is involved in the regulation of cell movement and of APP transcriptional activity [9]. On the other hand, many of the APPinteracting proteins may also possess a role in the regulation of APP processing, its transcriptional activation, and even in amyloid formation. In this scenario, the Cterminal domain of APP has a pivotal role due to the presence of the YENPTY motif that represents the docking site for multiple interacting proteins involved in cell signaling. Among others, ShcA and Grb2 apparently act through a different mechanism involving a specific phosphorylation step at Tyr 682, the precise regulation of which is still under investigation. Grb2 and ShcA may act independently from each other and APP has the capacity to recruit Grb2 directly or indirectly through Shc [13,67] (Fig. 2) [59]. Considering that in the Alzheimer’s disease brain there is a significant upregulation of the interaction between these adaptors and the APP C-terminal domain [44], and that the interplay between Grb2/APP and Grb2/ ShcA/APP may be involved in apoptotic mechanisms [58,59], it is conceivable that these two adaptors are implicated in negative aspects of APP signaling. At the same time, given the pathogenetic significance of the entanglement of protein–protein interaction around APP, it is likely that the exact comprehension of the regulatory mechanisms that activate the interplay between kinases, phosphatases, and intracellular signal through APP and its CTFs may open a completely new scenario for a therapeutic perspective for Alzheimer’s disease.

Acknowledgments We gratefully acknowledge the financial support by Telethon grant no. E1144, E.C. Contract no. LSHM-CT2003-503330/APOPIS, and Alzheimer Association USA IIRG-02-3976 given to GS.

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