Localization and Trafficking of Amyloid-β Protein Precursor and Secretases: Impact on Alzheimer's Disease.

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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-142730 IOS Press

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Localization and Trafficking of Amyloid-␤ Protein Precursor and Secretases: Impact on Alzheimer’s Disease

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Paula Agostinhoa,b,∗ , Anna Pliássovaa,b , Catarina R. Oliveiraa,b and Rodrigo A. Cunhaa,b

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a CNC-Center

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for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal of Medicine, University of Coimbra, Coimbra, Portugal

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Accepted 10 December 2014

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Keywords: A␤PP, A␤PP-derived fragments, ADAM10, amyloid-␤, BACE1, ␥-secretase, presenilin

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Abstract. Alzheimer’s disease (AD) affects almost 35 million people worldwide. One of the neuropathological features of AD is the presence of extracellular amyloid plaques, which are mainly composed of amyloid-␤ (A␤) peptides. These peptides derive from the amyloidogenic proteolytic processing of the amyloid-␤ protein precursor (A␤PP), through the sequential action of ␤and ␥-secretases. However, A␤PP can also be cleaved by a non-amyloidogenic pathway, involving an ␣-secretase, and in this case the A␤ formation is precluded. The production of A␤ and of other A␤PP catabolites depends on the spatial and temporal co-localization of A␤PP with ␣- or ␤-secretases and ␥-secretase, which traffic through the secretory pathway in a highly regulated manner. Disturbances on A␤PP and secretases intracellular trafficking and, consequently, in their localization may affect dynamic interactions between these proteins with consequences in the AD pathogenesis. In this article, we critically review the recent knowledge about the trafficking and co-localization A␤PP and related secretases in the brain under physiological and AD conditions. A particular focus is given to data concerning the distribution of A␤PP and secretases in different types of synapses relatively to other neuronal or glial localizations. Furthermore, we discuss some possible signals that govern the dynamic encounter of A␤PP with each group of secretases, such as A␤PP mutations, estrogen deprivation, chronic stress, metabolic impairment, and alterations in sleep pattern-associated with aging. The knowledge of key signals that are responsible for the shifting of A␤PP processing away from ␣-secretases and toward the ␤-secretases might be useful to develop AD therapeutic strategies.

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ALZHEIMER’S DISEASE: A MATTER OF ALTERED DYNAMICS OF PROTEINS During the last century, much of research has focused in studying the molecular pathogenesis of Alzheimer’s disease (AD), since this highly debilitating neurodegenerative disorder is the primary cause ∗ Correspondence

to: Paula Agostinho, Center for Neurosciences of Coimbra, University of Coimbra, 3004-517 Coimbra, Portugal. Tel.:+351 239820190; Fax:+351 239822776; E-mail: [email protected]. or E-mail: [email protected].

of dementia in the elderly and one of the major health problems. Nowadays, more than 35 million people live with AD and this number is estimated to double in the next 20 years; thus it is urgent for the scientific community, and also for the general population, to better understand the causes and molecular mechanisms of AD in order to find out therapeutic solutions to halt the constant increase of affected patients [1]. AD can be categorized into two main forms. The familial forms are less common (5% of the cases) and have an early onset (usually before 60 years age); their hereditary is linked to autosomal mutations in

ISSN 1387-2877/15/$27.50 © 2015 – IOS Press and the authors. All rights reserved

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the amyloidogenic pathway, and A␤PP mutations can result in increased A␤ production, mainly of A␤ with 42 amino acids (A␤42 ) that is more toxic and prone to aggregate than A␤40 (the most abundant form) [12, 13]. The spatial proximity of A␤PP with the different secretases in diverse stages of life and in pathological and non-pathological conditions is determinant for the pathway of A␤PP processing and A␤ production. The accumulation of A␤ peptides in the brain is a consequence of an altered balance between its synthesis, clearance, and aggregation rate. Although in normal conditions, the human brain produces considerable amounts of A␤ peptides, those quantities are much higher in AD patients, and they are approximately equivalent to 7 years of total A␤ production in healthy individuals [14]. Although the molecular triggers of AD are not clearly established, it is widely believed that A␤ peptides cause neuronal damage, mainly synaptotoxicity, and also affect the function of other brain cells, such as glia and endothelial cells, thus playing a crucial role in AD pathogenesis [15–17]. Several studies have reported that the levels of soluble A␤ peptides are superior to amyloid plaques, and that soluble A␤ correlates best with memory decline in AD patients [18, 19] and in AD animal models [20]. Thus, the original amyloid cascade hypothesis, which postulates that the A␤ deposits in plaques are the causative agent of AD [21], evolved to propose that soluble A␤ oligomers precede deposition and are the proximal cause of synaptic dysfunction and early cognitive impairment in AD [22, 23]. Although there is genetic and neurochemical evidence supporting the amyloid/A␤ hypothesis, it is becoming evident that AD pathogenesis is much more complex and that A␤ production/accumulation per se is unable to account for all AD features [24]. In fact, neuroimaging studies (PET scans) confirm the previous autopsy observations [25] showing that the amyloid deposits can be present in cognitively normal subjects, while some AD patients did not exhibit amyloid deposits [26, 27]. Also, the synaptic loss and the presence of tau hyperphosphorylated in tangles seem to be better correlated with disease severity than A␤ accumulation [28]. Moreover, transgenic mouse models of AD, which exhibit A␤ overproduction and accumulation as well as cognitive deficits, do not display neurodegeneration [29]. Another argument against the amyloid/A␤ hypothesis is that the several anti-amyloid drugs have failed in clinical phase III trials, and, although these anti-amyloid drugs were administered late in disease progression, the negative outcome is consistent with the notion that AD can be caused by

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the genes encoding the amyloid-␤ protein precursor (A␤PP) and in enzymes involved in its cleavage, presenilins 1 (PS1) and 2 (PS2) that make part of ␥- secretase complex [2, 3]. The sporadic forms of AD, which constitutes the majority of the cases, have a late-onset (over 65 years age); their causes are not completely clear but several risk factors have been identified, such as aging (the probability of developing AD increases from 10% under the age of 65 to 50% over 85 years age), diabetes and cardiovascular disease [4, 5], and the presence of apolipoprotein E (ApoE) ␧4 allele is the strongest genetic risk factor for sporadic AD [3, 6]. Recent genome-wide association studies identified other genes associated with the individual risk of developing AD, such as single-nucleotide polymorphisms for clusterin (also known as apolipoprotein J), ATP-binding cassette transporter A7 (ABCA7) and for phosphatidylinositol binding clathrin assembly protein (PICALM). The proteins codified by these genes are involved in amyloid-␤ (A␤) production and also in cholesterol and lipid metabolism which is disturbed in AD (reviewed in [7]). Both familial and sporadic forms of AD manifest as a series of mild cognitive impairments, deficits in short-term memory, loss of spatial memory, and emotional imbalances. As the disease progresses, these symptoms become more severe, leading to total loss of executive functions [8]. The neuropathological features of AD include the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles of hyperphosphorylated tau protein, and the loss of synapses, mainly in hippocampus and entorhinal cortex [4]. Since the description by Alois Alzheimer in 1907 [9] of the presence of darkly-stained amyloid plaques in the brain of an autopsied patient that had a progressive dementia and deterioration of cognitive function, it took almost 75 years to identify the major constituent of these plaques as a 40–42 amino acid peptide, termed A␤ [10]. The A␤ peptide is produced by endoproteolytic processing of a larger transmembrane protein, named A␤PP. The cleavage of A␤PP is a constitutive process mediated by secretases (␣-, ␤-, and ␥-secretase), which can generate A␤ peptides with variable length (39–43 amino acids) and also secreted ectodomain fragments, sA␤PP␤ or sA␤PP␣, and the A␤PP intracellular domain (AICD) [11, 12]. The formation of the different A␤PP fragments depends on the type of secretase that cleaves the extracellular A␤PP domain: the ␤-secretase (amyloidogenic) or the ␣-secretase (non-amyloidogenic, see below “A␤PP proteolysis and its catabolites”). An imbalance in the proteolytic cleavage of A␤PP, favoring

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AMYLOID-␤ PROTEIN PRECURSOR AβPP family: Structure and function

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and maturation and brain network function [38, 39]. APLP1 is only expressed in the brain, whereas APLP2 and A␤PP are distributed throughout the body. However, only A␤PP has the A␤ domain, and consequently only this protein family member can give rise to the A␤ that composes amyloid plaques in AD brain [40]. Moreover, given the participation of this protein in the molecular pathology of AD most of the existing knowledge is concerning to A␤PP. In humans, A␤PP is encoded by a gene located on chromosome 21 that was identified for the first time in 1987 [41]. A␤PP has at least three isoforms, A␤PP695, A␤PP751, and A␤PP770, which result from alternative splicing of exon 7 that encodes a Kunitz-protease inhibitor (KPI) domain and exon 8 that contains an OX-2 homology sequence. A␤PP695 lacks KPI and OX2, while A␤PP751 and A␤PP770 contain the KPI and KPI plus OX-2, respectively [42]. The A␤PP695 is the most abundant in the brain and is mainly present in neurons. The two longer A␤PP isoforms (A␤PP751 and A␤PP770 ) are mostly present in glial cells, such as astrocytes [43]. The A␤PP770 isoform also exists in brain vascular endothelial cells and can give rise to A␤ peptides and, consequently, to A␤ deposition in cerebral vessel walls, which origins cerebral amyloid angiopathy that is observed in more than 80% of AD patients [44]. In AD brain, it was reported that the expression of A␤PP695 mRNA is reduced, whereas the mRNA of A␤PP770 is increased [42]. Individuals with trisomy 21 (Down syndrome) or with point mutations in the A␤PP gene (familial cases of AD) habitually develop AD pathology [46]. Although A␤PP has been widely studied, the A␤PP functions are still unclear; and the use of genetic knockout or knockin models, involving A␤PP as well as APLP 1 and 2, have given better insight about the neuronal and systemic functions of these proteins, demonstrating unequivocally their involvement in development of the nervous system [47]. A␤PP has a large extracellular domain that functions as cell adhesion motif mediating cell-cell adhesion and migration, and such intercellular interactions are important in early phases of development for the generation of synaptic junctions [38, 48, 49]. Increasing evidence postulates that A␤PP participates in synaptogenesis, dendritic spine formation, synaptic vesicle and transmitter release, and synaptic plasticity and behavior [39, 50]. Besides the crucial role of A␤PP in synaptic formation and maturation, it also regulates intracellular calcium homeostasis, through the interaction with L-type calcium channels, which is crucial for intracellular signaling and synaptic transmission; thus A␤PP is

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A␤PP, which can give rise to A␤ peptides, belongs to a highly conserved protein family that also includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) in mammals. All the elements of this family are type 1 transmembrane proteins, resembling cell-surface receptors, and are composed by a large extracellular domain (N-terminal) that constitute about 88% of the total protein mass, a single membrane-spanning domain and a short cytoplasmic domain (C-terminal) of 47 amino acid residues [35]. A␤PP and A␤PP-like proteins share a sequence similarity in their extracellular domains, which contain the Kunitz protease inhibitor (KPI) domain and the E1 and E2 domains, but the highest sequence similarity between these proteins is within the small cytosolic domain that contains multiple motifs that have key roles in controlling the functions of these proteins [36, 37]. The function of A␤PP, and even more of APLP1/2, is not completely known, although it was first supposed that these proteins were functionally redundant due to their biochemical and processing similarities, there is evidence supporting that A␤PP and APLPs have diverged and might have distinct functions [38]. In the brain, A␤PP and APLPs are involved in cell migration, synaptogenesis, and synaptic plasticity, and consequently are crucial in brain development

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A␤-independent factors [24, 30, 31]. Thus, the idea that AD may be caused by A␤PP-derived fragments, and not necessarily only by A␤ peptides, has gained momentum [32], notably because it was shown that both extracellular and intracellular fragments of A␤PP can trigger neuronal damage [33, 34]. Since A␤PP and its metabolism play an important role both in familial and sporadic forms of AD, it seems crucial to understand where, when, and how A␤PP actually meets with the different secretases. Thus, a better insight about the synthesis, trafficking, proteolytic processing, and function of A␤PP and of its co-localization with the different secretases might be useful to better understand brain alterations that occur in AD. Accordingly, this review will address the individual properties of A␤PP and of the different secretases, but will mostly focus on the localization and the dynamics of A␤PP and of secretases, highlighting the current caveats that still need to be resolved to translate this knowledge into potentially novel therapeutic interventions in AD.

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C-terminus (residues 682–687 of A␤PP695 isoform) [61]. After endocytosis, A␤PP is delivered to endosomes and part of it is recycled to the cell surface and to the TGN, whereas a small fraction is degraded in lysosomes [35, 60]. Within the Golgi network, A␤PP can meet ␣-secretase or ␤-secretase, and thus it is likely that a part of A␤PP proteolysis occurs there [62]. The A␤PP trafficking is a process highly regulated by several cytosolic factors, such as the members of protein families: A␤PP-binding A (APBA, previously called MINT), A␤PP-binding B1 (APBB1, previously called Fe65) [63, 64], RAB GTPase and sorting nexins [65]. These trafficking factors usually interact with A␤PP through its YENPTY motif. The trafficking of A␤PP can also be regulated by the low-density lipoprotein receptor family that also act as receptors for ApoE, which allelic polymorphisms are strongly associated with the onset of AD [65, 66]. Interestingly, PS1 (catalytic component of the ␥-secretase complex) can also regulate the intracellular trafficking of A␤PP, and, accordingly, reduced levels of PS1 increase the maturation and cell surface accumulation of A␤PP [67, 68]. The phosphorylation of A␤PP at S655 and T668 (based on A␤PP695 numbering) in the intracellular domain and the A␤PP glycosylation also regulate the trafficking of this transmembrane protein [41, 69, 70]. Interestingly, it was reported that phospho-A␤PP is enriched at the plasma membrane of nerve terminals, and accumulates in damaged regions of AD brain [71]. It is known that in neurons, which are polarized cells, A␤PP traffics down the axon and dendrites via anterograde transport machinery to target their terminals where the secretases involved in A␤PP proteolysis reside as well [72, 73]. Thus, the A␤ released synaptically might contribute to synaptic dysfunction and be one of the sources of extracellular amyloid deposits, which usually surround the dystrophic neurites [74].

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AβPP trafficking and localization

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currently considered to be a key modulator of synaptic plasticity and neuronal viability [16, 50, 51]. For these reasons, it is thought that the loss of A␤PP function might contribute to disturbed neuronal communication and, consequently, to cognitive impairment. The overall structure of A␤PP suggests that it functions as a receptor, and several binding proteins have been proposed for A␤PP with various functional implications. For example, A␤ and F-spondin (neuronal secreted glycoprotein) can bind A␤PP at the extracellular domain with a possible action of ligand [52, 53], while the intracellular A␤PP domain, mainly through the YENPTY motif, interacts with various adaptor proteins that regulate A␤PP trafficking or control of signaling pathways activation (see below; [37, 54, 55]). The possible action of A␤ on A␤PP suggests a putative pathological feed-forward mechanism linking A␤ production and accumulation to abnormalities in A␤PP processing and function, which in turn would trigger the progressive neuronal loss that occurs in early phases of AD [56]. It is also likely that the physiological functions of A␤PP are primarily mediated by its secreted ectodomains fragments, sA␤PP␣ and sA␤PP␤, that are generated through the action of ␣-secretase and ␤-secretase, respectively. Additionally, APLP 1 and APLP2 can suffer proteolytic processing by secretases, releasing ecodomains with physiological functions [11, 57].

A␤PP, like other proteins, is biosynthesized in the endoplasmic reticulum (ER) and transported via the constitutive secretary pathway from the ER, through the Golgi apparatus/trans-Golgi network (TGN), to the cell membrane. As A␤PP traffics through the secretory pathway, it undergoes post-translational modifications, including O- and N-glycosylation, ubiquitination, phosphorylations, and tyrosine sulfations [58]. On the way to the plasma membrane, A␤PP is packaged into post-Golgi transport vesicles, through the assistance of a heterotetrameric adaptor protein complex AP4 that interacts with a specific cytosolic sequence of A␤PP to facilitate its recruitment into transport vesicles [59]. However, only a small portion (about 10%) of nascent A␤PP molecules reaches the plasma membrane and most of them localize in the TGN at steady-state [60]. At the plasma membrane, the A␤PP that is not proteolytically processed undergoes endocytosis within minutes of arrival at the plasma surface, due to the presence of a “YENPTY” internalization motif near the

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AβPP proteolysis and its catabolites A␤PP can suffer proteolytic processing via two major pathways (Fig. 1): 1) The non-amyloidogenic pathway is mediated by an ␣-secretase that cleaves within the A␤ region, (hindering the release of A␤ peptides) and generates a large soluble ␣-secreted A␤PP (sA␤PP␣) fragment that can be released to the extracellular milieu and the membrane-bound C-terminal fragment (␣-CTF or C83) that can be further proteolyzed by ␥-secretase (a multimeric enzyme complex) to generate AICD and a p3 peptide that is rapidly degraded. 2) The amyloidogenic pathway of A␤PP proteolysis is mediated by ␤-secretase (BACE1) within

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from the neuronal A␤PP695 isoform, epigenetically regulates the protein transthyretin that is involved in the binding and clearance of A␤ peptides [77]. The proteolytic processing of A␤PP per se is a highly regulated event and several regulatory components of secretases have been identified. Since A␤PP and secretases involved in its proteolysis are membrane proteins, it is expected that the cell membrane lipid-composition controls the A␤PP proteolysis, as well as secretases activity. In fact, there is evidence that the amyloidogenic A␤PP processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts, and changes in cholesterol levels alters the distribution of A␤PP-cleaving enzymes within the membrane [7, 78]. Depletion of cholesterol prevents the amyloidogenic pathway, reducing the formation of A␤, and in general shifts the A␤PP processing toward a preferential non-amyloidogenic processing [79]. However, it remains controversial whether the treatment with cholesterol-lowering statins has benefits or not to AD patients [78]. Interestingly, it was reported that A␤PP controls cholesterol turnover, biosynthesis, and hydroxylation, which are events crucial for synaptic function [80]. Besides cholesterol, other membrane lipids affect the targeting of A␤PP and secretases to lipid rafts and, consequently, the A␤PP proteolysis. The polyunsaturated fatty acid, docosahexaenoic acid that decreases de novo cholesterol synthesis, promotes the non-amyloidogenic A␤PP processing [7]. In human brain of early AD stages, it was reported

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the ectodomain and leads to the formation of soluble ␤-secreted A␤PP (sA␤PP␤) and the membraneanchored A␤PP ␤-carboxyl-terminal fragment (␤CTF or C99). The ␤-CTF is further cleaved by the ␥-secretase within the lipid bilayer, resulting in the production of amyloidogenic A␤ peptide with variable length (39–43 amino acid long) and the A␤PP intracellular domain (AICD) [11, 60]. The A␤PP metabolites generated from both pathways were recognized to have important physiological brain functions. The sA␤PP␣ was shown to have neuroprotective proprieties and to be involved in neurites outgrowth and also increases long-term potentiation (LTP), a phenomenon underlying memory and learning. Although the sA␤PP␤ has the same sequence of sA␤PP␣ apart from the last 16 amino acids of C-terminal, it does not affect LTP and the neuroprotective effects of sA␤PP␤ are less potent [57]. Curiously, both sA␤PP␤ and sA␤PP␣ could afford protection against the A␤ oligomers that cause synaptic dysfunction and neuronal death. By contrast, the A␤ monomers seem to share similar properties with sA␤PP␣ and are endowed with neurotrophic and neuroprotective properties, being involved in neural progenitor cells proliferation and in synaptic transmission [57, 75]. The AICD, which is released intracellularly in both amyloidogenic and non-amyloidogenic pathways, is an important regulator of gene expression controlling a diverse range of genes, including A␤PP itself, the amyloid-degrading enzyme neprilysin, and aquaporin-1 [43, 76]; indeed, it was recently shown that AICD, derived specifically

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Fig. 1. Schematic representation of the two pathways of amyloid-␤ protein precursor (A␤PP) proteolytic processing. A) The non-amyloidogenic pathway involves a first cleavage of A␤PP by an ␣-secretase that generates the soluble fragment (sA␤PP␣) and a membrane-bound C-terminal fragment (C83) that is further proteolyzed by the ␥-secretase complex to generate the AICD (A␤PP intracellular domain) fragment and the p3 peptide. B) The amyloidogenic pathway of A␤PP proteolysis is mediated by a ␤-secretase, leading to the formation of soluble ␤-secreted A␤PP fragment (sA␤PP␤) and the membrane-anchored fragment (C99). The C99 is further cleaved by the ␥-secretase and generate the AICD fragment and the amyloidogenic A␤ peptide (39-43 amino acid long). 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408

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SECRETASES INVOLVED IN THE PROTEOLYTIC PROCESSING OF A␤PP

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domain rich in cysteines, a transmembrane domain, and a short cytoplasmic domain (C-terminal) [88]. ADAM10 is found mainly in the Golgi, where it is supposed to be inactive, as a pro-enzyme. After the cleavage of the signal peptide, ADAM10 enters the secretory pathway and suffers N-glycosylation, thus becoming an active protease [88, 89]. This activated form is mainly localized at the plasma membrane, supporting the idea that A␤PP cleavage by ␣-secretases occur mainly at the cell surface; however, there is also evidence of ADAM10 activity in the Golgi apparatus and in transport vesicles, so a small pool of A␤PP proteolysis may also occur in these subcellular compartments (see Fig. 2). Tight regulation of ADAM10 levels at the plasma membrane is crucial to control the enzyme activity and, consequently, its function. The removal of ADAM10 from the plasma membrane is mediated by clathrin-dependent endocytosis, involving a clathrin adaptor AP2 protein that controls the availability of this secretases in the synapse [90]. In the brain of AD patients, it was reported an increased association between ADAM10 and AP2; thus it is likely that the reduced ␣-secretase activity in this disease could be attributed to a deficiency in ADAM10 exocytosis/endocytosis processes rather than to an alteration in ADAM10 levels [90, 91]. Another protein involved in ADAM10 trafficking and synaptic anchoring is the synapse-associated protein-97 (SAP97), a member of the MAGUK family of protein scaffolds. SAP97 was shown to target ADAM10 to postsynaptic membrane of excitatory synapses by a direct interaction through it Src homology 3 (SH3) domain. Accordingly, it was shown that the impairment of ADAM10/SAP97 association affects ADAM10 localization in postsynaptic membranes and, consequently, decreases its action on synaptic substrates, such as on A␤PP or Ncadherin that are also involved in cell adhesion and migration and also in dendritic spine stabilization [91, 92]. Alterations in ADAM10/SAP97 association was reported in the brain of AD patients [91]; curiously, the disruption of the association between SAP97 and ADAM10 in vivo using peptides led to the generation of a non-transgenic animal model of AD [93]. In vitro studies using chemical compounds to induce LTP and long-term depression, in hippocampal neuronal cultures, showed that LTP induces ADAM10 endocytosis and decreases its levels at cell surface through ADAM10 association with AP2; whereas long-term depression augments ADAM10 synaptic insertion and stimulates its activity through the association of SAP97 with this secretase. These data suggest that ADAM10

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α-Secretases

The ADAM (a disintegrin and metalloproteinase) family is formed by proteins that have both features from cell adhesion molecules and proteases. Among different important roles, they are involved in fertilization, angiogenesis, neurogenesis and also in the proteolysis of some substrates, like the A␤PP, the receptor for advanced glycation endproducts (RAGE) and Notch receptor [82–84]. The ␣-secretase cleavage of A␤PP releases an N-terminal extracellular domain that is soluble, the sA␤PP␣, that have neurotrophic and neuroprotective properties. It is known that quite a few elements of the ADAM family exhibit ␣-secretase-like activity. In fact, ADAM9, ADAM10, and ADAM17, which are type I transmembrane proteins, have been shown to act as ␣-secretases. Among these proteases, ADAM10 is considered a key protease in the processing of A␤PP, segregating significant amounts of an N-terminal extracellular domain of sA␤PP␣ in vivo [85]. On the other hand, several studies have confirmed that ADAM17, also named TACE (tumor necrosis factor-␣-converting enzyme), likely affects regulated, but not constitutive, A␤PP ␣-cleavage [16, 85, 86]. In neurons, ADAM10 is the physiological constitutive ␣-secretase for A␤PP [86, 87], and this secretase also plays a central role in the developing brain by controlling neural Notch signaling [87]. ADAM10 belongs to the zinc proteinase family and its typical structure consists of a prodomain, a catalytic domain with a zinc binding sequence, a disintegrin-like

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that the increased proportions of saturates/n3 and phospholipids/cholesterol in lipid rafts from entorhinal and frontal cortices render up liquid-ordered microdomains, which promotes the encounter between A␤PP and BACE and, consequently, the amyloidogenic processing of A␤PP [81]. Both the non-amyloidogenic and the amyloidogenic pathways are crucial to guarantee normal brain function, and the A␤PP processing by ␣-secretase (non-amyloidogenic pathway) or by ␤-secretase (amyloidogenic pathway) greatly depends on colocalization between A␤PP and these secretases, which in turn is dependent on their subcellular co-distribution [65]. Thus, a fuller understanding of the mechanisms responsible for regulating the intracellular trafficking and processing of A␤PP and related secretases are crucial to better understand AD pathogenesis.

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levels at the cell membrane are dynamically regulated by activity-dependent synaptic plasticity, and that SAP97 and clathrin adaptor AP2 (both proteins binds to C-terminal of ADAM10) are critical links between synaptic function and ADAM10 activity and, consequently, A␤PP proteolytic processing [90]. Alterations of ADAM10 activity or of its spatial and temporal localization with A␤PP, related with changes in synaptic plasticity or occurring with aging, might be the trigger for a switch from a non-amyloidogenic to an amyloidogenic processing of A␤PP, intensifying the production of A␤ peptides and, consequently, the onset of AD. Recently, two rare mutations in the pro-domain of ADAM 10 (Q170H and R181G) were identified to be linked with sporadic AD, since these mutations reduce ADAM10 activity and shift A␤PP processing toward ␤-secretase-mediated cleavage, increasing A␤ production and accumulation and reactive gliosis [94]. Thus, it is tempting to speculate that strategies that augment the ADAM10/␣-secretase activity and,

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Fig. 2. Representation of putative localization of amyloid-␤ protein precursor (A␤PP) and secretases (␣, ␤, and ␥) involved in the A␤PP proteolytic processing. A␤PP, ␣-secretase, ␤- secretase, and ␥-secretase, after translation in the endoplasmic reticulum, are transported from the TGN and secretory vesicles to plasma membrane. Part of these proteins is re-internalized via the endosomal system, cycling between TGN, transport vesicles and plasma membrane, and other part is proteolytic processed. A) The cleavage of A␤PP by ␣-secretase and further by ␥-secretase (non-amyloidogenic pathway) occurs mainly at the plasma membrane, only a small portion of A␤PP is cleaved in the transport vesicles. The non-amyloidogenic A␤PP cleavage generates secreted A␤PP fragments, sA␤PP␣ with neuroprotective proprieties, and also the p3 fragment and AICD. B) The cleavage of A␤PP by ␤-secretase and further by ␥-secretase (amyloidogenic pathway) occurs not only at the plasma membrane but also in the endosomal/lysosomal system, where the acidic pH potentiates the ␤-secretase activity. The amyloidogenic A␤PP cleavage, besides forming sA␤PP␤ and AICD, generates A␤ peptides, which form oligomers that are thought to cause synaptotoxicity, thus being the causative agent of AD.

consequently, hinder A␤ production are beneficial for AD. However excessive activation of these secretases should be avoided because ADAM10 is not A␤PP specific, and it can also cleave substrates that are related with tumor development [95]. β-Secretases The ␤-site A␤PP-cleaving enzyme 1 (BACE1), also known as aspartyl protease 2 (Asp2), was identified in 1999 as the major ␤-secretase enzyme for A␤PP. BACE1 cleaves A␤PP at the N-terminal, producing a secreted sA␤PP␤ fragment and the membranebound C99 fragment that is subsequently cleaved by ␥-secretase to generate A␤, thus be involved in amyloidogenic pathway of A␤PP processing. Other aspartic acid protease was further identified, the BACE2 that shares about 64% amino acid similarity with BACE1 and is also capable of cleaving the A␤PP. This homolog of BACE1 seems to have also

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with GGA and promotes the transport of BACE1 from endosomes to TGN, while non-phosphorylated BACE1 enters a direct recycling route to the plasma membrane [65, 106]. BACE1 and A␤PP can follow similar trafficking routes and co-localize within neuronal endosomes, thus providing perfect conditions for ␤-secretase activity. The convergence of A␤PP and BACE1 is a rate-limiting event for the amyloidogenic processing of A␤PP cleavage. Neuronal dendrites are endowed with vesicles containing A␤PP/BACE1, which secretion is dependent on neuronal activity and seems to occur largely in physiologic conditions [107]. This is supported by the presence of significant intracellular amounts of A␤, whose accumulation augments with age, and seems to be correlated with the disruption of neurites cytoarchitecture and neuronal loss [108, 109]. However, there is evidence supporting that the endocytosis of A␤PP and BACE1 are controlled by two different processes: BACE1 internalization to early endosomes is found to be regulated by the GTPase ADP ribosylation factor 6 (ARF6), whereas A␤PP internalization is by a clathrin-dependent endocytic pathway [110, 111]. Therefore, it is believed that A␤PP and BACE1 are separately internalized from the plasma membrane through distinct routes and then merge at the early endosomes, where the A␤PP can be cleaved by BACE1. Accordingly, it was reported that BACE1 can sort from ARF6-positive endosomes, helped by its DISLL motif (amino acids 496–500), to RAB-5 positive early endosomes where it cleaves A␤PP [112]. The highest levels of BACE1 mRNA are found in the brain cortex region. BACE1 was shown to be concentrated in pre-synaptic terminals of neurons [113, 114], suggesting a role for BACE1 in synaptic function. In fact, BACE1 is present in CA1 and CA3 regions of the hippocampus and has important physiological functions in synaptic transmission and plasticity [115, 116]. Moreover, at birth, elevated levels of BACE1 being transported throughout the axons were reported, suggesting that this secretase may be also related to myelinization onset by Schwann cells [91, 117]. Although under healthy conditions BACE1 is present almost exclusively in neurons, an increase of BACE1 levels was reported to occur in astrocytes with aging and following stress and inflammatory conditions, as well as in the brain of AD patients and AD animal models [118–120]. Additionally, in brain endothelial cells, an upregulation of BACE1 under ischemic-like conditions of oxygen and glucose deprivation [121] and prolonged endoplasmic reticulum

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␤-secretase activity; however BACE2 is not involved in A␤ production as it cleaves within the A␤ domain near [37, 96]. Besides, the levels of BACE2 in the brain are approximately 10-fold lower when compared to BACE1 levels [97, 98]. BACE1 is a 501 amino acid long type I transmembrane protease and has two active site motifs, both necessary to its correct function. This enzyme has a luminal active site, which provides a correct topological orientation for A␤PP cleavage, while near the C-terminus there is a single transmembrane domain [99]. The immature BACE1 containing a short prodomain that is removed by autocatalyse or by furin and furin-like proteases in the Golgi apparatus, leading to its maturation and increased ␤-secretase activity [97, 100]. In addition, BACE1 can be N-glycosylated, promoting its proper folding and stability. The mature BACE1 is exported from TGN, via secretory vesicles to the plasma membrane, mainly to lipid rafts, where A␤PP is also present. Once in the plasma membrane, BACE1 can be internalized into the endosomes, whereby it can be recycled to the cell membrane or transferred to late endosomal/lysosomal compartments to be degraded. Since BACE1 has maximal activity at acidic pH, it is more active in the acidic subcellular compartments of the secretory pathway, such as in the TGN and endosomes/lysosomes [96, 100, 101]. Thus, BACE1-mediated cleavage of A␤PP preferentially occurs in early and late endosomes and/or lysosomes. There are several known modulators that regulate the BACE1 trafficking between TGN, plasma membrane, and endosomes, such as the family of Golgi-localized ␥-adaptin ear-containing ADP ribosylation factor binding proteins (GGA), retromer complex, and the SNX family (reviewed in [65]). The cellular prion protein (PrPC ), which is known to be involved in prion disorders, has also been point out to be involved in AD because PrPC can either regulate the BACE1 activity or bind A␤, causing its internalization [102–105]. Curiously it was reported that PrPC interacts with the prodomain of BACE1 and retains the secretase in the TGN, inhibiting its trafficking to the cell surface and endosomes; since A␤PP nonmutated (wild-type) is primarily cleaved by BACE1 in endosomes whereas the cleavage of A␤PP with the Swedish mutation (A␤PPswe associated with familial AD) occurs primarily within the TGN, it was proposed that PrPC might be a key protective player against sporadic AD [103]. The phosphorylation state of BACE1 also determines its trafficking, and it was shown that phosphorylation of BACE1 enhances it interaction

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a functional heterodimer each contributing with a conserved aspartate residue essential for ␥-secretase catalytic activity, where full-length PS is degraded. NCT is a type I transmembrane glycoprotein considered to be involved in the recognition and binding of substrates acting as the ␥-secretase receptor. The seven-transmembrane APH-1 interacts with NCT to form a stable intermediate in an early assembly stage of the ␥-secretase complex, whereas the transmembrane components of PEN2 are responsible for the endoproteolytic processing of PS, conferring ␥-secretase activity to the complex [65, 120, 132]. All of these four components (PS1/2, NCT, PEN2, APH-1) are necessary for ␥-secretase activity and deficiency in any of these factors dramatically affects the enzymatic activity [65]. The aspects involved in the assembly, maturation, and trafficking of ␥-secretase complex are not totally established. However, it is known that after the synthesis of PS, NCT, APH-1, and PEN2 in the ER, these components are incorporated into stable complexes. The formation of the complex begins with the association of APH-1 and NCT to form an early intermediate sub-complex, and then this heterodimer binds and incorporate the full-length PS. The final step of the assembly occurs in the ER and Golgi compartment when PEN2 binds to a transmembrane domain of PS, driving the conversion of the full-length PS into active heterodimers of NTF/CTF of PS. During the trafficking of this complex through Golgi/TGN, NCT is glycosylated, thus transforming the ␥-secretase complex into its mature form. The mature ␥-secretase complex in large part (95%) cycle between the ER and Golgi, whereas only a minority (5%) of ␥-secretase complex is transported to the plasma membrane. At the plasma membrane, ␥-secretase can then undergo endocytosis to endosomes, and subsequent trafficking to late endosomes/multivesicular bodies or to lysosomes to be degraded [65, 133]. Besides its key catalytic function in the ␥-secretase complex, PS1 also modulates the trafficking of several transmembrane proteins, including the other ␥-secretases components (NCT, APH-1, and PEN2) and the substrate A␤PP. PS1 exerts trafficking regulation through the interaction with several trafficking modulator proteins, such as RAB family members, phospholipase D1 (PLD1), and A␤PP and, reciprocally, these modulators of trafficking may also regulate the transport of PS1 [65, 134]. For example, PLD1 interacts with PS1 and the overexpression of PLD1 promotes PS1 accumulation at the plasma membrane [134]; A␤PP can also reciprocally regulate the

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γ-Secretase complex

The ␥-secretase can catalyze the final of two subsequent cleavages of A␤PP to release A␤ (in amyloidogenic pathway) or p3 (a 3 kDa product, in non-amyloidogenic pathway) and also generates AICD in both pathways of A␤PP cleavage. The term “␥secretase” was used for the first time in 1993 to describe the proteolytic cleavage in the transmembrane domain of A␤PP and other proteins with membrane-spanning domain [128], and it took over a decade to identify all of the components of this secretase [129, 130]. The ␥-secretase is a high molecular weight multisubunit protease complex, composed of at least four integral membrane proteins: presenilin (PS, two mammalian homologs as PS1 and PS2), nicastrin (NCT), presenilin-enhancer 2 (PEN2), and anterior pharynxdefective-1 (APH-1). The PS1 and PS2 are integral membrane proteins that span membranes multiple times with the large hydrophilic loop and the Nand C-terminal oriented to the cytosol [130, 131]. These termini undergo endoproteolytic cleavage to generate PS amino-terminal fragments (NTFs) and carboxi-terminal fragments (CTFs), which can form

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stress [122] was reported. In the brain of AD patients, the levels of BACE1 are markedly elevated in 50% of patients and its increased levels in cerebrospinal fluid at early AD phases could provide a biomarker of this disease [123–125]. Indeed, it was proposed that as soon as amyloid accumulation rises, the levels of BACE1 increase and contribute to accelerate A␤ production and, consequently, to enlarge amyloid deposition. Thus, it is likely that BACE1 is actively involved in AD progression and is not just one of the numerous degenerative changes in terminal disease brains [126]. Given that the overexpression or downregulation of BACE1 induces or inhibits A␤PP processing and A␤ generation, both in vitro and in vivo, and that the BACE1 is upregulated in AD brain, it is likely that the BACE1 blockade or the genetic silencing might be a therapeutic strategy for AD. However, the complete inhibition of BACE1 was shown to be hazardous, since this secretase, like others, is not A␤PP-specific and also cleaves other proteins, such as neuregulin 1, p-selectin glycoprotein ligand-1, ST6GAL1, and ␤subunits of voltage-gated sodium channels [65, 90]. In contrast, the partial reduction of BACE1 activity was shown to ameliorate AD-like pathology, making BACE1 an excellent target for therapeutic intervention in AD [124, 127].

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than the secretase complex that contains PS2, thus PS1/␥-secretase is likely to generate also more AICD than the one containing PS2 [150]. However, it is widely recognized that autosomal mutations in PS1 or PS2 genes are one of the possible causes for familial AD [14]. In conditional double knockout mice lacking both presenilins (PS1/PS2) in postnatal forebrain, it was observed impairments in hippocampal synaptic plasticity and memory as well as neuronal death [151, 152]. The genetic conditional inactivation of PS1/PS2 in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaffer pathway reveals that PS1/PS2 regulate neurotransmitter release and LTP induction via modulation of intracellular Ca2+ -release in presynaptic terminals [153]. Interestingly, it was reported that PS1 overexpression promotes synaptic dysfunction in a ␥-secretase- and A␤- independent manner. This evidence suggest that PS1, outside the ␥-secretase complex, has a crucial role in spine morphology and synaptic plasticity during both normal and pathological aging [154, 155]. Accordingly, it was stated that PS1 is necessary to improve excitatory synaptic transmission, mainly after a decrease in neuronal activity [55, 156]. Because ␥-secretase has been pointed out to be a therapeutic target in AD, numerous ␥-secretase inhibitors (GSIs) orally-bioavailable and brain penetrant have been developed that effectively inhibit ␥-secretase cleavage, and the GSIs have been conceptualized as “A␤ production inhibitors”. However, it was shown that GSIs also interfere with the Notch signaling by hindering the proteolysis of Notch1 receptor, which cause several undesirable cellular effects and, ultimately, hamper the successful implementation of GSIs as therapeutic agents for AD [157, 158]. Thus, several compounds that act as ␥-secretase modulators (GSMs) were developed to be evaluated as potential AD drugs. The GSMs potentially lowered A␤ peptides, mainly the A␤42 , without affecting Notch signaling or the accumulation of A␤PP-CTF. Some of nonsteroidal anti-inflammatory drugs, such as ibuprofen, indomethacin, and sulindac sulfide, act as ␥-secretase modulators that cause a decrease in the formation of A␤42 and concomitant increase in shorter A␤ species, mainly A␤38 [159, 160].

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trafficking of PS1 and of other ␥-secretase components [135, 136]. In fact, it was shown that A␤PP deficiency results in a faster transport of PS1 from the TGN to the cell membrane, increasing the levels of PS1 at the plasma membrane surface at steady state, with this effect reversed by restoring A␤PP levels [134]. In addition, the transport of PS1, as well as BACE1, along the axon can be mediated by A␤PP [137, 138]. Interestingly it was reported that PS1 preferentially binds immature BACE1 and is involved in its maturation and, thus, functions as a regulator of both ␥- and ␤-secretases activities [138, 139]. The postsynaptic protein Arc was shown to be physically associated with PS1 in early/recycling endosomes within dendrites of excitatory neurons. Arc-positive endosomes can traffic PS1, A␤PP, and BACE1, suggesting the involvement of Arc in A␤ formation [140]. Although the activity of PS1/␥-secretase is mostly present in neurons, it was reported that the presence of PS1 and NCT in activated astrocytes and microglia upon several paradigms of brain injury [141]. The function of PS1 in the ␥-secretase proteolytic activity was first identified in neuronal cultures derived from PS1-deficient mouse embryos, where it was shown that PS1 is crucial to generate A␤ peptides with 40–42 amino acids [142] and, thus, PS1 has been considered as an important AD drug target [142, 143]. One year later, it was established the role of PS1 in the ␥-secretase processing of protein receptor Notch [142, 145], whose ligands, Delta and Jagged, can also undergo ␥-secretase intramembrane proteolysis [146]. The Notch receptor upon ligand binding to extracellular domain can be cleaved by ␥-secretase, releasing an intracellular domain of Notch (NICD) that has activity in the nucleus through binding to transcription factors, being involved in cell fate specification and differentiation in various systems and is also active in the mature brain where is thought to be required for long-term memories formation [147]. Similarly, the intracellular domain of A␤PP (AICD), which is released from the cell membrane by ␥-secretase, undergoes translocation to the nucleus and may function as a transcriptional regulator (see above “A␤PP proteolysis and its catabolites”, [76]). Although the majority of AICD is degraded, it is possible that under certain conditions, e.g., A␤PP overexpression and/or ␥-secretase upregulation, a significant amount of AICD may fulfill its function and cause neuron-specific cell death, thus contributing for AD pathogenesis [148, 149]. Several cellular and biochemical studies indicate that PS1-containing ␥-secretase complex generates significantly more A␤ peptide from the A␤PP substrate

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WHEN AND WHERE DOES A␤PP MEET THE DIFFERENT SECRETASES The parameters that correlate better with cognitive impairment in early phases of AD are the loss

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to internalization of A␤PP and production of intracellular A␤? Interestingly, the distribution of A␤PP and secretases in different types of synapses relatively to other neuronal or glial localizations and their different co-localization has been scarcely studied. Recently, our group reported that A␤PP is located in astrocytic membranes (gliosomes) and enriched in hippocampal nerve terminals (synaptosomes). Furthermore, a sub-synaptic fractionation approach showed that A␤PP is particularly enriched in the presynaptic active zone, although it is also present in the post-synaptic [172]. In addition we reported that glutamatergic terminals have relatively more A␤PP than GABAergic terminals [172]. These findings are in agreement with the preferential accumulation of A␤ in glutamatergic terminals in the AD brain [173, 174] and also explain the predominant susceptibility of glutamatergic synapses in an animal model of AD based on the intracerebral administration of soluble A␤1–42 [175]. However, further studies should be designed to test if A␤ pathology initially affects a particular subtype of neurons and progresses in a neuronal-specific mode, since there are some reports at odds with the particular initial affliction of glutamatergic terminals. In fact, it was initially proposed that cholinergic terminals were the most vulnerable, followed by the glutamatergic terminals and finally, the GABAergic terminals [173, 176]; however, it was later shown that the glutamatergic neurons are particularly susceptible to A␤ [175, 176], whereas GABAergic neurons seem to be mainly affected around amyloid plaques in the AD brain [177]. Although the presence of higher amounts of A␤PP in glutamatergic terminals is suggestive of a prominent A␤PP metabolization in these particular terminals, it is the relative co-localization of A␤PP and of ␣and/or ␤-secretases that will determine if A␤PP will be metabolized to yield A␤. The secretase that determines A␤ production, BACE1, was proposed to exist mainly in neurons and was shown to be present in presynaptic active zone of cortical nerve terminals (see above, “␤-secretases”; [113, 114]). However, it is still unknown if ␤-secretases have a particularly abundant localization in any particular type of nerve terminals. Interestingly, although ␤-secretases are considered to be mainly neuronal, there is evidence that BACE1 can also be located in astrocytes upon stressful conditions and in AD conditions [118, 119]. Furthermore, it was reported that cultured astrocytes exposed to A␤42 peptides display increased levels of BACE1 and A␤PP and also of sA␤PP␤ and A␤40 fragments, indicating a feedforward mechanism of astrocytic A␤ production [178].

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of synapses and the increased production of soluble A␤ peptides (reviewed in [17]). Usually the concept of synaptic loss is associated with alterations in structure and communication between the preand post-synaptic elements; however, accumulating evidence supports the existence of a bidirectional communication between neurons and astrocytes, which give rise to the concept of ‘tripartite synapse’ to specify the astrocyte as the third element of synapses (reviewed in [161, 162]). The astrocytes: (1) enwrap most synapses, (2) provide metabolic fuel avidly required by synapses to function, (3) actively remove excitatory neurotransmitters, namely glutamate from synapses, (4) participate in ion homeostasis, (5) shape synaptic volume, (6) feedback and adjust synaptic strength through release of gliotransmitters, (7) control radical stress, (8) handle most of the lipid metabolism, (9) mediate synapse elimination in the developing and adult brain, and (10) control microglia and actively participate in formatting the inflammatory milieu affecting synapse function and pruning [162–164]. In accordance with these key functions, it is expected that changes in astrocyte number and/or functions would influence the integrity and activity of neuron-astrocytes network, with impact on behavior output such as cognitive function [162, 165, 166]. Although reactive astrocytes have been observed around amyloid plaques since AD was first described, the role of these glial cells in the onset of AD cardinal features, such as memory impairment, synaptic loss, and the production/accumulation of A␤ peptides has been scarcely investigated. In a transgenic AD mice model (3xTgAD), early astrocytic shrinkage that was associated with the cognitive deficits and memory loss was observed [167]; and recently it was shown that the GABA released from reactive astrocytes causes memory impairment [168]. A␤ peptides cause astrocyte activation reducing their capacity to uptake glutamate [169, 170], which can cause excitotoxicity and subsequent neuronal damage and memory impairment. Accordingly, it was shown that the blockade of astrocytic glutamate uptake triggers spatial memory deficits in rats [171]. This supports the idea that in AD, the third element of synapses, the astrocyte, is also responsible for synaptic plasticity disruption and, consequently, for memory impairment. One of the major unanswered issues in AD is why only some particular synapses begin degenerating in early phases of this disease. Do they have a particular phenotype, i.e., are they glutamatergic, cholinergic, or GABAergic? Are they endowed with a particular combination of A␤PP and secretases? Are they more prone

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of amyloid plaques in familial forms of AD. Another recent study reported that long-term ovariectomized rats exhibit an upregulation of A␤PP and secretases in the hippocampal CA3 region and a switch in A␤PP processing from non-amyloidogenic to amyloidogenic pathway [184]. Thus, the estrogen deprivation might be a signal that favors A␤PP and BACE1 interaction, and, consequently, A␤ production, which is in agreement with the fact that menopause is a risk factor for the onset of AD. It was also observed that there is a diurnal variation of the levels of the soluble A␤PP fragments, sA␤PP␣, sA␤PP␤, A␤40 and A␤42 in the cerebrospinal fluid and in the blood of healthy adults [185]. The amplitude of this circadian variation diminishes with aging and with the presence of amyloid plaques in the brain, and this age-related alteration is more dependent on the trafficking of A␤PP rather than on the trafficking of ␣and/or ␤-secretases [185]. Since there are alterations in the sleep pattern upon aging, it would be interesting to investigate whether sleep deprivation or fragmentation might be a trigger for the shifting of A␤PP processing from ␣-secretase to the ␤-secretase pathway. In this respect, it was reported that age-associated sleep fragmentation reduces A␤ clearance, leading to its accumulation in the brain, potentially contributing to AD onset [186]. Additionally, work shifts might impact A␤ production and accumulation; however epidemiological studies on the relationship between practices of night work shifts and AD incidence are missing. Chronic stress has also been pointed out as a trigger of AD development [187, 188]. Thus, we can ponder that chronic stress might also impact on A␤PP processing pathways by ␣- or ␤-secretases. This assumption is supported by a study showing that repeated restraint stress upregulates the levels of BACE1 and A␤PP, favoring ␤-amyloidogenesis in the hippocampus of female, but not of male, transgenic 5XFAD mice modeling AD, at the pre-pathological disease stage [190]. The relation between stress and the control of A␤PP processing is further heralded by the observation that glucocorticoids increase the gene expression of A␤PP and of BACE1 and, consequently, the production of A␤ in cultured astrocytes and in astrocytes of middle-aged mice [191]. Increasing evidence supports the notion that AD is primarily a metabolic disease with molecular features in brain tissue that resemble diabetes mellitus and other peripheral insulin resistance disorders (reviewed in [192, 193]). However, few data are available exploring how metabolic dysfunction might affect the pathways of A␤PP processing. In a transgenic AD mouse

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This suggests that astrocytes, besides being important for A␤ clearance and degradation [179], can also produce A␤ and potentially contribute to the synaptic A␤ burden in early AD. However, further studies are required to test if astrocytes indeed contribute to the production of the A␤ that accumulates in the synaptic clef triggering synaptotoxicity. The production of A␤ not only depends on the colocalization of A␤PP and ␤-secretases, but is also critically regulated by the co-presence of ␣-secretases, which ensure a non-amyloidogenic metabolism of A␤PP. It was reported that one of the constituents of ␣-secretases, ADAM10, is mostly concentrated in postsynaptic region of excitatory synapses [90], which is in accordance with results obtained by our group comparing the relative density of ADAM 10 in subsynaptic fractions of mice cortical nerve terminals (unpublished data). Again, the eventual different localization of ␣-secretases in different types of nerve terminals is currently unknown. Interestingly, in agreement with the increased recognition of astrocytes in the emergence and progression of AD [15], the presence of ADAM10 and ADAM17 has been reported in human astrocytes [180, 181]. Furthermore, both human astrocytoma cells activated by interleukin-1␤ and mouse astrocytes in culture exposed to glutamate receptor agonists, were able to produce the neuroprotective sA␤PP␣ fragment [180, 182]. Likewise, brain damage conditions that cause glial activation trigger the expression of the A␤PP processing proteins PS1 and NCT in astrocytes [141]. Overall, this evidence suggests that astrocytes, mainly when activated, can express A␤PP and the secretases responsible for the amyloidogenic and non-amyloidogenic pathway of A␤PP processing. Thus, it is likely that the status of astrocytes activation will determine if astrocytes might produce either the neuroprotective sA␤PP␣ fragments or the A␤ peptides that can contribute to synaptotoxicity. The amyloidogenic and non-amyloidogenic processing of A␤PP depend on the dynamic encounter of A␤PP with ␤- or ␣-secretases, which is ultimately regulated by the dynamic of the trafficking of these different proteins. However, the signals governing the asymmetric dynamic encounter of A␤PP with each group of secretases still remain to be unraveled. However, some remarkable pioneering experiments have dwelt on this subject, tentatively identifying particular experimental conditions that impact on A␤ production. Thus, it was shown that the Swedish mutation of A␤PP increases the affinity of BACE1 for A␤PP [183] and, consequently, promotes A␤ production, which is in accordance with the premature and large accumulation

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ACKNOWLEDGMENTS The study about the synaptic localization of A␤PP and secretases started with a project supported by FCT (PTDC/SAU-NMC/114810/2009). We thank for financial support to DARPA and Santa Casa da Misericórdia. Authors’ disclosures available online (http://j-alz. com/manuscript-disclosures/14-2730r1).

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(Fig. 2). Herein, we cover some of the relevant aspects of A␤PP and secretase trafficking, localization, and function in physiological and in AD conditions. Given the participation of A␤PP and secretases in AD pathogenesis, and since the memory deficits in AD are correlated with synaptic dysfunction and loss, it would be useful to investigate the synaptic and sub-synaptic distribution of A␤PP and secretases (␣, ␤, and ␥) across different types of nerve terminals in different brain regions and if their distribution changes in AD conditions. The definition of the specific localization of these proteins would undoubtedly be of crucial importance for the development of novel therapeutic approaches in AD.

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CONCLUSIONS

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model (5XFAD), it was shown that diabetic conditions of insulin deficiency increase the levels of A␤PP and BACE1, and also of C99 fragment [194]. Metabolic and blood oxygenation deficits, which are usually associated with neuronal hypoactivity, can also cause BACE1 upregulation, increasing the formation of sA␤PP␤ and A␤ peptides [195, 196]. In aged monkey and in AD human cerebral cortices, the upregulation of BACE1 occurs mainly in dystrophic axonal neurites of neurons that are in close proximity to the vasculature [197]. In addition, a study from the same group showed that transgenic mice modeling AD display a co-localization of BACE1 with A␤PP and with PS1 in dystrophic neurites of different types of neurons, such as GABAergic, glutamatergic, cholinergic, and catecholaminergic [153]. Since A␤PP and its processing enzymes, particularly BACE1, is essential for A␤ production, the knowledge of how A␤PP and secretases are distributed in the synapses that are initially affected in AD could be useful for the development of effective therapeutic strategies that interfere with the interaction between A␤PP and secretases. Likewise, the identification of the key signals that are responsible for the shifting of A␤PP processing away from the ␣-secretases and toward the ␤-secretase pathway would offer additional therapeutic opportunities to interfere with the abnormal production of A␤ in early AD. Particular attention ought to be dedicated to A␤PP metabolism in tripartite synapses, since synaptoxicity seems to be the key initial event in early AD.

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A␤PP plays a crucial role in the pathophysiology of AD in large part due to its sequential proteolytic cleavage by particular secretases (␣- or ␤- and ␥-secretases) that result in the generation of A␤ peptides. This protein can be proteolyzed by a ␤-secretase/amyloidogenic pathway or ␣secretase/non-amyloidogenic pathway (Fig. 1); while in the former, A␤, the putative agent causing synaptic dysfunction and loss in AD, is produced, there are other secreted A␤PP, sA␤PP␣ and sA␤PP␣, and AICD fragments that are formed during A␤PP cleavage, whose putative contribution to the onset or progression of AD remains to be elucidated. A␤PP undergoes tightly regulated trafficking that determines its localization, in cell surface or in intracellular compartments, and also A␤PP co-localization with the different secretases, and consequently, the sort of A␤PP proteolytic processing

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The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: implications for Alzheimer's disease.

In vitro streptozotocin model for modeling Alzheimer-like changes: effect on amyloid precursor protein secretases and glycogen synthase kinase-3.

Impact of Vitamin D on amyloid precursor protein processing and amyloid-β peptide degradation in Alzheimer's disease.

Function of amyloid and amyloid protein precursor.

Impact of amyloid precursor protein hydrophilic transmembrane residues on amyloid-beta generation.

Subcellular localization of amyloid precursor protein in senile plaques of Alzheimer's disease.

Beta A4 amyloid protein and its precursor in Alzheimer's disease.

Mutations in amyloid precursor protein gene and disease.

Amyloid precursor protein and amyloid precursor-like protein 2 in cancer.

Combined deletions of amyloid precursor protein and amyloid precursor-like protein 2 reveal different effects on mouse brain metal homeostasis.

Mint proteins are required for synaptic activity-dependent amyloid precursor protein (APP) trafficking and amyloid β generation.

Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses.

Localization of Alzheimer beta A4 amyloid precursor protein at central and peripheral synaptic sites.

Synaptic and sub-synaptic localization of amyloid-β protein precursor in the rat hippocampus.

Tyrosine Binding Protein Sites Regulate the Intracellular Trafficking and Processing of Amyloid Precursor Protein through a Novel Lysosome-Directed Pathway.

Amyloid precursor protein and neural development.

An abnormality of plasma amyloid protein precursor in Alzheimer's disease.

Amyloid-β precursor protein synthesis inhibitors for Alzheimer's disease treatment.

Immunohistochemical colocalization of amyloid precursor protein with cerebrovascular amyloid of Alzheimer's disease.

Localization of amyloid precursor protein in selective postsynaptic densities of rat cortical neurons.

Secretion of the beta-amyloid precursor protein.

Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein.

MicroRNA-135a and -200b, potential Biomarkers for Alzheimer׳s disease, regulate β secretase and amyloid precursor protein.

Association and release of the amyloid protein precursor of Alzheimer's disease from chick brain extracellular matrix.