SEARCH

SEARCH BY CITATION

Keywords:

  • α-secretase;
  • ADAM proteases;
  • Alzheimer’s disease;
  • APP

Abstract

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

J. Neurochem. (2012) 120 (Suppl. 1), 34–45.

Absract

‘Secretase’ is a generic term coined more than 20 years ago to refer to a group of proteases responsible for the cleavage of a vast number of membrane proteins. These endoproteolytic events result in the extracellular or intracellular release of soluble metabolites associated with a broad range of intrinsic physiological functions. α-Secretase refers to the activity targeting the amyloid precursor protein (APP) and generating sAPPα, a soluble extracellular fragment potentially associated with neurotrophic and neuroprotective functions. Several proteases from the a disintegrin and metalloproteinase (ADAM) family, including ADAM10 and ADAM17, have been directly or indirectly associated with the constitutive and regulated α-secretase activities. Recent evidence in primary neuronal cultures indicates that ADAM10 may represent the genuine constitutive α-secretase. Mainly because α-secretase cleaves APP within the sequence of Aβ, the core component of the cerebral amyloid plaques in Alzheimer’s disease, α-secretase activation is considered to be of therapeutic value. In this article, we will provide a historical perspective on the characterization of α-secretase and review the recent literature on the identification and biology of the current α-secretase candidates.

Abbreviations used

amyloid-β

AD

Alzheimer’s disease

ADAM

a disintegrin and metalloproteinase

AJ

adherens junctions

APP

amyloid precursor protein

EGF

epidermal growth factor

GPCR

G-protein coupled receptor

MMP

matrix metalloproteinase

PC

proprotein convertase

PKC

protein kinase C

PMA, phorbol 12-myristate 13-acetate; RIP

regulated intramembrane proteolysis

SAP97

synapse-associated protein-97

TIMP

tissue inhibitors of metalloproteinase

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the first cause of dementia in the aged population. The exact mechanisms triggering neurodegeneration remain unclear but characteristic neuronal inclusion bodies implicating specific proteins have been identified and dictate the current molecular classification of the different neurodegenerative diseases (Dickson 2009; Duyckaerts et al. 2009). In AD, the amyloid-β (Aβ) peptides represent the core components of the senile plaques, the lesions invariably found in the neocortex and hippocampus of the AD brain (Selkoe 2001). In the amyloidogenic pathway, the amyloid precursor protein (APP) is sequentially cleaved by the protease β-secretase/BACE1 and by the γ-secretase proteolytic complex to produce various Aβ peptides, including the most abundant isoforms Aβ1-40 and Aβ1-42. Importantly, APP can also undergo a non-amyloidogenic proteolytic cleavage by α-secretase within the Aβ sequence, which thereby precludes Aβ generation (Checler 1995; Marambaud and Robakis 2005; De Strooper and Annaert 2010).

The etiology of AD is complex mostly because of its strong genetic heterogeneity (Lambert and Amouyel 2007). The study of rare early onset familial forms of the disease, however, has identified autosomal-dominant mutations in the APP gene, a seminal observation that indisputably strengthened the notion that Aβ is a causative factor in AD (Pastor and Goate 2004). Aβ peptides can also form small soluble oligomers, which have been proposed to represent neurotoxic entities in AD. Indeed, Aβ oligomers can affect synaptic activity and hippocampal long-term potentiation, a mechanism potentially relevant to the invariant synaptic and neuronal loss observed in the AD brain (Walsh and Selkoe 2007). In this context, the vast majority of the AD research is currently focusing on interventions aimed at lowering cerebral Aβ levels and aggregation. Approaches aimed at inhibiting β- or γ-secretase are actively pursued (Golde et al. 2010). These approaches, however, have encountered major challenges in the past few years because of the difficulty of developing clinically suitable inhibitors. Furthermore, γ-secretase is now known to target a large number of proteins, such as Notch, classic cadherins, or Ephrins, and thus its pharmacological inhibition is expected to lead to undesirable side-effects.

Another clinically relevant approach is to promote APP α-secretase cleavage. α- and β-secretases under specific conditions may compete for APP cleavage and this competition may determine whether Aβ will be generated or not (Postina et al. 2004; Kim et al. 2008). Furthermore, the α-secretase-derived soluble APP N-terminal fragment, sAPPα, has been proposed to be associated with neurotrophic and neuroprotective functions, further supporting the therapeutic value of increasing APP α-secretase cleavage. α-Secretase has already been the subject of several excellent and recent reviews (e.g. Lichtenthaler 2011; Vincent and Checler 2011). In this manuscript, our goal is to provide a more comprehensive historical perspective on the approaches that led to the identification of the different α-secretase candidates and to review the literature on their biological functions. The mechanisms of regulation in vitro and in vivo of α-secretase and their relevance for AD therapy will be reviewed in another article of this special issue.

APP α-secretase cleavage

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

APP α-secretase cleavage occurs in the center of the Aβ peptide sequence between Lys-16 and Leu-17 (Esch et al. 1990; Anderson et al. 1991; Wang et al. 1991). The precise site where the cleavage takes place is believed to be principally determined by an α-helical conformation and the distance (12–13 residues) of the hydrolyzed bond from the membrane (Sisodia 1992). α-Secretase shedding of APP leads to the production of a membrane-anchored carboxy-terminal fragment named C83 and to the extracellular release of the large soluble fragment sAPPα. sAPPα is secreted constitutively into the culture medium from almost all cell types. Stimulation of protein kinase C (PKC) by phorbol esters was shown to increase sAPPα release, demonstrating that APP α-secretase cleavage can be either constitutive or regulated (i.e. inducible), further implying that different α-secretase proteases may exist (Caporaso et al. 1992; Buxbaum et al. 1993; Hung et al. 1993). The search for α-secretase identity was eased by the finding that membrane metalloendopeptidases (Allsop et al. 1991; McDermott and Gibson 1991; Roberts et al. 1994) and more specifically members of the a disintegrin and metalloproteinase (ADAM) family could be responsible for the α-secretase activities. Indeed, the use of an inhibitor of the ADAM and matrixin families of proteases was shown to inhibit the regulated secretion of APP (Arribas and Massague 1995; Arribas et al. 1996). Since then, at least three members of the ADAM family were found to be strong candidates for the α-secretase-mediated shedding of APP, namely ADAM17, ADAM10, and ADAM9.

The ADAMs

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

The ADAMs represent a family of transmembrane and secreted proteins with endoproteolytic activities and involved in a broad range of physiological and pathological processes. Indeed, by shedding the ectodomains of various membrane proteins, such as growth factors, cytokines, or receptors, the ADAMs have emerged as critical players in cell growth, adhesion, and migration, but also in cell-cell communication and extracellular or intracellular signaling. ADAM17 (tumor necrosis factor-α convertase), for instance, is responsible for the proteolytic activation of TNF-α and epidermal growth factor (EGF) receptor ligands, which are regulators of several fundamental functions, such as inflammation or cell growth during development or cancer (Blobel 2005; Edwards et al. 2008). ADAM10, another important member of the ADAM family, is required for the proper function of Notch, Eph/ephrin, or classic cadherins. ADAM10-mediated proteolysis of these substrates is a pre-requisite for their subsequent regulated intramembrane proteolysis (RIP) by the presenilin/γ-secretase complex and the production of intracellular domains with signaling and transcriptional functions (Marambaud and Robakis 2005).

The ADAMs: an overview

ADAMs are characterized by the presence of conserved amino-acid domains, which include an N-terminal signal sequence, required for directing the proteins to the secretory pathway, followed by a prodomain, responsible for proper protein folding, a metalloprotein domain, a desintegrin domain, a cystein-rich region, an EGF-like domain (except for ADAM10 and ADAM17), a transmembrane domain, and a cytoplasmic domain (Blobel 2005; Edwards et al. 2008). The prodomain is removed during intracellular trafficking in the Golgi by the action of proprotein convertases (PCs) or autocatalytic processes. Thirty-eight members of the ADAM family from diverse species are listed in the current databases, 21 genes being found in human. The diversity of this protein family is increased by alternative splicing of several ADAM genes. The ADAMs are divided in two groups, the catalytically active group, which contains proteases with a Zn-binding active site and includes ADAM10 and ADAM17, and a catalytically inactive group, which includes proteases lacking a functional Zn-binding active site, and thus acting via other mechanisms, such as protein folding or protein interaction (Edwards et al. 2008).

ADAM activities are regulated by protein interactions with specific tissue inhibitors of metalloproteinases (TIMPs) (Baker et al. 2002). For instance, ADAM10 is inhibited by two members of the TIMP family, TIMP1 and TIMP3 (Amour et al. 2000). ADAM10 activity is also negatively controlled by another protein interaction implicating the protein RECK (reversion-inducing cystein-rich protein with Kazal motifs), a mechanism potentially involved in the nervous system development (Muraguchi et al. 2007). ADAMs are also functionally regulated by signal transduction events. ADAM activities, like α-secretase activities, are either constitutive or regulated by signaling events implicating G-protein coupled receptors (GPCRs), second messengers, or intracellular calcium. Multiple receptor ligands and direct activators of PKC are known to stimulate ADAM-mediated shedding of several substrates. Although the mechanisms of control of ADAM activities by these signaling events are not entirely clear because they could implicate complex and very indirect mechanisms of protein maturation and trafficking (e.g. see Doedens and Black 2000), several studies have identified specific pathways. For instance, PKC-stimulated shedding of the cellular prion protein or TrkA, two targets of ADAM17, was reported to be dependent on Thr-735 phosphorylation within ADAM17 cytoplasmic domain (Diaz-Rodriguez et al. 2002; Alfa Cisse et al. 2007) and to implicate ERK1/MEK signaling in the PKC-mediated processing of the cellular prion protein (Cisse et al. 2011b). Another example is the demonstration that dynamin-dependent endocytosis can regulate ADAM10 activity by controlling surface expression of mature ADAM10 and formation of an ADAM10 C-terminal fragment produced by ADAM9 or ADAM15 (Cisse et al. 2005; Parkin and Harris 2009; Tousseyn et al. 2009; Carey et al. 2011).

The biological functions of ADAM10 and ADAM17

In this section, we mainly focus our attention on the physiology of the main α-secretase candidates, ADAM10 and ADAM17. For more information on the general physiology of the other members of the ADAM family, the reader is directed to the previous reviews (Blobel 2005; Edwards et al. 2008).

ADAM10

Gene deletion in mice has provided valuable insights into the physiological functions of the different ADAMs. To date, knockout (KO) mouse models for at least 13 different ADAMs have been generated. ADAM10 deficiency in mice leads to embryonic lethality at E9.5 and severe developmental defects of the CNS and heart, a phenotype resembling the one observed in mice deficient for Notch signaling (Hartmann et al. 2002). Notch is a cell surface receptor critically involved in transcription control during development. Notch is a type I protein that undergoes a series of proteolytic events by different enzymatic activities. γ-Secretase cleaves Notch within its transmembrane sequence to allow the release of Notch intracellular domain, a proteolytic fragment that translocates to the nucleus to control transcription via binding and activation of the transcription factor CBF1, Su(H) and Lag1 (Kopan and Ilagan 2009). In order for the γ-secretase cleavage of Notch to occur, an earlier cleavage is required (the S2 cleavage) and is likely to be mediated by ADAM10 (Rooke et al. 1996; Pan and Rubin 1997; Hartmann et al. 2002; van Tetering et al. 2009).

This mechanism of sequential endoproteolysis initiated by ADAM shedding and resulting in the γ-secretase-dependent release of an intracellular domain with signaling properties has now been observed for numerous other type I proteins, including the Notch ligand Delta1 (Six et al. 2003), classic cadherins (Marambaud et al. 2002, 2003; Maretzky et al. 2005a; Reiss et al. 2005), EphrinB2 (Georgakopoulos et al. 2006), or L1 (Maretzky et al. 2005b). In many instances, the ADAM involved in this process is ADAM10. Indeed, classic cadherins are another example of type I proteins sequentially targeted by ADAM10 and RIP. Classic cadherins, including epithelial (E)- and neural (N)-cadherins, belong to the cadherin superfamily of cell–cell adhesion molecules. Cadherins are found in adherens junctions (AJ) where they control structural tissue integrity (Nelson 2008). Presenilin-1 directly associates with the juxtamembrane domain of E-cadherin in epithelial cells (Georgakopoulos et al. 1999; Baki et al. 2001), a mechanism that controls the γ-secretase-dependent proteolysis of E-cadherin (Marambaud et al. 2002). Like for Notch and APP, E-cadherin processing by γ-secretase is preceded by its ectodomain shedding by ADAM10 (Maretzky et al. 2005a). Upon cell–cell dissociation, E-cadherin is cleaved by ADAM10 to produce a membrane bound C-terminal fragment (Marambaud et al. 2002; Maretzky et al. 2005a), which is then targeted by γ-secretase to lead to AJ disassembly (Marambaud et al. 2002).

During the early postnatal period, CNS cadherins participate in the brain circuitry establishment by controlling axon guidance and synaptogenesis (Arikkath and Reichardt 2008). Cadherin expression is maintained at mature synapses in the adult brain, where they constitute a main structural component regulating synaptic plasticity. Changes in synaptic strength, a process that coordinates synaptic plasticity and memory formation, require the remodeling of the synaptic architecture and most likely disassembly of cadherin AJ at the synapses. Presenilin-1 was found in complexes with brain E- and N-cadherins and localizes at synaptic contacts (Georgakopoulos et al. 1999). Stimulation of the NMDA receptor promotes the γ-secretase processing of N-cadherin in primary neurons, suggesting the physiological relevance of this pathway during synaptic activation (Marambaud et al. 2003). ADAM10 also localizes at synaptic terminals (Janes et al. 2005; Marcello et al. 2007) and is responsible for N-cadherin ectodomain shedding, in general (Reiss et al. 2005; Uemura et al. 2006), and more specifically at the synapse (Malinverno et al. 2010). Furthermore, synaptic activity appears to be positively coupled to ADAM10-mediated N-cadherin processing in primary hippocampal neurons (Malinverno et al. 2010). Thus, regulated ADAM10 activity at the synapse is under the control of synaptic activity via a mechanism that may implicate NMDAR. Interestingly, neuronal activity was also found to regulate Aβ production by stimulating β-secretase (Kamenetz et al. 2003). Whether synaptic activity also promotes APP α-secretase cleavage via ADAM10 to compete with β-secretase and to interfere with synaptic Aβ production awaits further investigation.

ADAM17

Like ADAM10, ADAM17 targets a broad range of substrates implicated in several physiological mechanisms. ADAM17 was initially reported to be responsible for the proteolytic activation of the membrane precursor of TNFα (Black et al. 1997; Moss et al. 1997), a cytokine critically involved in inflammation and with relevance in diseases such as rheumatoid arthritis, cancer, or AD. ADAM17 may also be involved in the ectodomain shedding preceding the RIP of p75 neurotrophin receptor to control apoptosis (Srinivasan et al. 2007). ADAM17 is critically involved in EGF signaling by targeting several mediators of this pathway, including HB-EGF or amphiregulin (Sahin et al. 2004). Indeed, ADAM17 gene depletion in mice results in perinatal lethality accompanied by severe defects in heart development, a phenotype resembling the one observed in mice KO for EGF receptor, TGFα, HB-EGF, or amphiregulin (Blobel 2005). A recent study reported that ADAM17 can cleave neuregulin-1 type III to negatively control peripheral nervous system myelination (La Marca et al. 2011).

ADAM17 was found in several studies to behave as an inducible protease regulated by PKC (Horiuchi et al. 2007). It appears that in many instances, different ADAMs are involved in the constitutive or regulated shedding activities, depending on the substrates targeted and conditions of stimulation (e.g. PKC or calcium influx) (Horiuchi et al. 2007). L1 and APP are typical example of such a mechanism. ADAM10 cleaves both proteins under constitutive conditions, while ADAM17 may take over as the main sheddase under PKC-stimulated conditions (Maretzky et al. 2005b).

α-Secretase and ADAM17

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

Buxbaum et al. (1998) first proposed that ADAM17 was involved in the regulated APP α-secretase cleavage. They demonstrated that ADAM17 could directly cleave in vitro a peptide encompassing the α-secretase cleavage site of APP. More interestingly, studies using fibroblasts derived from ADAM17 KO mice demonstrated that ADAM17 is the predominant α-secretase for the PKC-dependent regulated secretion of sAPPα (Buxbaum et al. 1998; Merlos-Suarez et al. 1998). However, the constitutive formation and secretion of sAPPα was unaffected in these cells supporting the existence of two classes of α-secretase (Buxbaum et al. 1998). In human primary neuronal cultures, ADAM17 inhibition using CP-661,631 prevented PKC-mediated regulated secretion of sAPPα without impacting total Aβ levels (Blacker et al. 2002). Regulated α-secretase cleavage can also be triggered by activation of several GPCRs coupled to the Gq protein and thus to PKC activation (Refolo et al. 1989; Nitsch et al. 1992, 1998; Davis-Salinas et al. 1994; Lee et al. 1995; Kojro et al. 2006). Activation of the M1-type muscarinic acetylcholine receptor using the agonist AF267B was found to stimulate α-secretase activity via ADAM17 in vivo in the 3xTg-AD mouse model (Caccamo et al. 2006). Thus, ADAM17 is considered to be responsible in large part for the regulated α-secretase proteolysis of APP. ADAM17, however, might also be responsible to some extent for the constitutive α-secretase activity because its over-expression in HEK293 cells results in an increase of constitutive sAPPα release (Slack et al. 2001). Recent evidence also indicates that pharmacological inhibition of ADAM17 in CHO cell cultures and in Tg2576 mice resulted in a reduction in sAPPα levels, further showing that ADAM17 is involved in APP α-secretase cleavage in vivo (Kim et al. 2008).

A systematic examination of ADAM gene expression in rodent CNS showed that ADAM10 is widely expressed whereas ADAM17 had a more restricted expression pattern in the hippocampus (Karkkainen et al. 2000). No change in ADAM17 expression in AD brains was found (Skovronsky et al. 2001). ADAM17 expression in the human brain was detected in distinct neuronal populations including pyramidal neurons of the cerebral cortex and granular cell layer neurons in the hippocampus. In AD brains, ADAM17 positive neurons were found to often colocalize with amyloid plaques, supporting the notion that this metalloprotease may be involved in AD pathogenesis (Skovronsky et al. 2001).

α-Secretase and ADAM10

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

ADAM10 also possesses the ability to proteolytically cleave in vitro a synthetic peptide at the α-secretase site between Lys-16 and Leu-17. Furthermore, increased basal and PKC-stimulated α-secretase activities were observed in HEK293 cells over-expressing ADAM10, suggesting that ADAM10 contributes to both constitutive and regulated α-secretase activities (Lammich et al. 1999). Treatments with pituitary adenylate cyclase-activating polypeptide, a neuropeptide that binds the GPCR pituitary adenylate cyclase-activating polypeptide type I receptor, was found to increase sAPPα by preferentially activating ADAM10, further supporting that ADAM10 could also be involved in the regulated α-secretase shedding of APP (Kojro et al. 2006). Studies in embryonic fibroblasts generated from ADAM10 deficient mice revealed, however, that loss of ADAM10 expression does not completely block sAPPα (Hartmann et al. 2002). ADAM10, at least in embryonic fibroblasts, was therefore not essential for APP α-secretase cleavage, suggesting that several proteases might be implicated in sAPPα secretion in this cell system (Hartmann et al. 2002). In contrast, primary neuronal cultures from ADAM10 deficient mice or treated with ADAM10 siRNA showed reduced APP α-secretase cleavage, suggesting that ADAM10 is the genuine constitutive α-secretase in neurons (Jorissen et al. 2010; Kuhn et al. 2010). Furthermore, over-expression of ADAM10 in mice transgenic for APP (V717I) led to increased secretion of sAPPα and a reduction of Aβ. In contrast, over-expression of a catalytically inactive ADAM10 mutant led to a strong reduction of sAPPα levels, and to an increase of the number and size of amyloid deposits in the brain of the V717I-APP mice (Postina et al. 2004).

In situ hybridization in the adult mouse brain for ADAM10 showed a moderate expression throughout the telencephalon and diencephalon, including the parietal and piriform cortex, the hippocampus, and the ventromedial hypothalamus (Karkkainen et al. 2000). Analysis of ADAM10 expression in mouse and human brain by in situ hybridization also showed that ADAM10 was co-expressed with APP in human cortical neurons (Marcinkiewicz and Seidah 2000). Furthermore, by immunohistochemistry, ADAM10 was found associated with diffuse and neuritic plaques in AD brains and a reduction in the number of ADAM10 immunoreactive neurons was observed (Bernstein et al. 2003).

α-Secretase and ADAM9

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

ADAM9 (MDC9 or meltrin gamma) possesses an α-secretase-like activity. Early studies reported that ADAM9 expressed in COS cells can increase the secretion of basal sAPPα and enhanced sAPPα secretion upon phorbol 12-myristate 13-acetate (PMA) treatment (Koike et al. 1999). However, ADAM9 was not able to cleave an APP peptide at the physiologically relevant α-secretase site, suggesting therefore that ADAM9 is most likely not responsible for the α-secretase processing of APP. However, ADAM9 relatively efficiently processed an APP peptide and might have some role in APP processing in particular conditions and cell types. The ADAM9 cleavage of APP occurs in a sequence (HHQK) which apparently plays a role in inducing microglia (Giulian et al. 1998; Roghani et al. 1999). Furthermore, ADAM9, as well as ADAM15, have been identified as responsible for the shedding of ADAM10 (Tousseyn et al. 2009) and thus might be indirectly involved in APP shedding. Nevertheless, analysis of mice lacking ADAM9 showed no differences in the production of α-secretase-derived fragments in cultured hippocampal neurons, arguing against a major role of ADAM9 as the genuine α-secretase in mice (Weskamp et al. 2002).

Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

Comparative studies between the three main α-secretase candidates can provide insights into the role played by each ADAM in the constitutive and regulated α-secretase activities. In a comparative study, over-expression in COS-7 cells or silencing in human glioblastoma A172 cells of ADAM9, ADAM10, and ADAM17 showed that these three ADAMs have a constitutive and a regulated α-secretase-like activity in these cell types (Asai et al. 2003). Antisens-mediated knockdown of ADAM10 and ADAM17 in SH-SY5Y cells showed that ADAM10 was mostly involved in the constitutive α-secretase activity (Allinson et al. 2004). In another comparative study using neuronal cells, knockdown of ADAM9, ADAM10, and ADAM17 in HEK293 and SH-SY5Y cells led to the conclusion that ADAM10, but not ADAM9 or ADAM17, was essential for the constitutive APP α-secretase cleavage, and that ADAM9 and ADAM17 did not compensate for the loss of ADAM10. Indeed, lentiviral knockdown of ADAM10 in primary murine cortical neurons reduced sAPPα production, whereas knockdown of ADAM9 and ADAM17 did not affect sAPPα levels, showing that both ADAM9 and ADAM17 were not required for the constitutive APP α-secretase cleavage in primary neurons. Finally, in SH-SY5Y cells transfected with ADAM9, 10, or 17 siRNAs and stimulated or not with PMA, only ADAM17 silencing suppressed the PMA-induced increase of sAPPα, further showing that, whereas ADAM10 is responsible for constitutive α-secretase, ADAM17 appears to be required for regulated α-secretase in neurons (Kuhn et al. 2010). It is important to note, however, that under specific stimulation conditions, such as activation of the purinergic receptor P2X7, regulated α-secretase shedding of APP may implicate metalloprotease activities that are not carried out by ADAM9, ADAM10, and ADAM17 (Delarasse et al. 2011).

Other α-secretase candidates

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

Besides ADAM9, ADAM10, and ADAM17, other ADAM members have been suggested to possess α-secretase-like activity toward APP. ADAM8 was shown to cleave a peptide corresponding to APP as well as APP itself after transfection in HEK293 cells (Naus et al. 2006). ADAM19 was also proposed to be involved in the constitutive α-secretase activity (Tanabe et al. 2007). Members of the matrix metalloproteinase family (MMP) like MMP-9 (Talamagas et al. 2007; Vaisar et al. 2009) or membrane type matrix metalloproteinase-1 (MT1-MMP), MT3-MMP, and MT5-MMP (Higashi and Miyazaki 2003; Ahmad et al. 2006) were also proposed to have α-secretase-like activity. Other proteases were suggested to control α-secretase-like activities, such as the proteasome (Marambaud et al. 1997), PC7 (Lopez-Perez et al. 1999), or glycosylphosphatidylinositol-anchored aspartyl proteases (Komano et al. 1998; Sambamurti et al. 1999). The consensus is now that these proteases might not be directly involved in the shedding of APP but rather represent indirect regulators of APP α-secretase cleavage by ADAM17 or ADAM10. For instance, ADAM activation requires the removal of the inhibitory prodomain by PCs, such as furin or PC7. LoVo colon carcinoma cells are furin-deficient cells devoid of regulated PKC-dependent sAPPα secretion. PC7 and ADAM10, but not ADAM17, where described to contribute to the constitutive sAPPα secretion in these cells (Lopez-Perez et al. 2001). PC7 participation in APP α-secretase cleavage was reinforce by the observation that its over-expression in HEK293 cells led to an increase in sAPPα secretion (Lopez-Perez et al. 1999). It appeared that PC7 was not directly responsible for APP α-secretase cleavage but instead was involved in ADAM10 prodomain cleavage and ADAM10 activation. Indeed, over-expression of PC7 or furin in HEK293 cells increased the maturation of ADAM10, which resulted in enhanced α-secretase activity (Anders et al. 2001). Infection of a furin adenovirus induced sAPPα production in LoVo cells and induced maturation of ADAM10 and ADAM17 (Hwang et al. 2006). Furin activity alone might not be sufficient for the effective maturation of ADAM17 because in vitro and in vivo cleavage assays indicated that paired basic amino acid cleaving enzyme 4, PC5/6, PC1, and PC2 could directly cleave ADAM17, indicating that others PC were likely to be also involved in ADAM17 maturation (Srour et al. 2003). Nevertheless, further evidence supporting the importance of furin came from in vivo results showing that furin injection into the brain of Tg2576 mice increased α-secretase activity and reduced Aβ generation (Hwang et al. 2006). Furthermore, furin mRNA levels were found to be significantly lower in the brains of AD patients and Tg2576 mice (Hwang et al. 2006).

Mechanisms of regulation of APP α-secretase cleavage

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

The mechanisms of regulation of α-secretase cleavage are not entirely understood because they implicate complex and indirect mechanisms of signal transduction or protein maturation and trafficking. It appears that the nature of the ADAM involved in the α-secretase shedding is determined by several factors, which include the cell types in which the proteolysis is occurring, the specific mechanisms used to induce the regulated α-secretase cleavages, or the specific substrate to cleave. For example, IGF-1-induced ectodomain shedding of APP and amyloid beta (A4) precursor-like protein 2 (APLP2) are mediated by different α-secretases. ADAM10 is the enzyme responsible for IGF-1-induced processing of APP, whereas ADAM17 mediates amyloid beta (A4) precursor-like protein 2 (APLP2) cleavage upon IGF-1 stimulation (Jacobsen et al. 2010). In addition, regulation of α-secretase ectodomain shedding of APP can be modulated at multiple levels via mechanisms that control the transcription, phosphorylation, maturation, or trafficking of the different ADAMs involved. Interleukin-1β, for instance, enhanced α-secretase shedding of APP in SK-N-SH cells and in mouse primary neurons by up-regulating ADAM17 levels (Tachida et al. 2008).

Phosphorylation of ADAM17 at Thr-735 is another way to control ADAM17 trafficking and maturation (Soond et al. 2005). ERK was shown to be involved in this phosphorylation event at Thr-735 in ADAM17 (Diaz-Rodriguez et al. 2002). Muscarinic receptor activation by carbachol was reported to trigger ADAM17 Thr-735 phosphorylation and to increase ADAM17 activity, yet without modifying its trafficking to the membrane (Alfa Cisse et al. 2007; Cisse et al. 2011a). Insulin and IGF-1 both can increase the ectodomain shedding of APP in SH-SY5Y cells (Adlerz et al. 2007), and IGF-1 also induced PKC-dependent phosphorylation of ADAM17 (Jacobsen et al. 2010). Other mechanisms of regulation include signaling by ERK1/2 and PI3K, which control the pituitary adenylate cyclase-activating polypeptide-stimulated APP α-secretase cleavage (Kojro et al. 2006). Activation of another kinase p38-MAPK through the use of phosphatase inhibitors, such as cantharidin, was reported to lead to an increase in the Thr phosphorylation of ADAM17 and to an increase in ADAM17 cell surface expression. This phenomenon was not observed after activation of PKC by PMA, suggesting that different mechanisms were involved (Killock and Ivetic 2010).

Cholesterol, an essential component of cell membranes, has been proposed to influence the α-secretase shedding of APP. Indeed, increased α-secretase activity mediated by a reduction of plasma membrane cholesterol could be explained by effects on ADAM10 (Kojro et al. 2001). Activation of liver X receptors, known regulators of cholesterol homeostasis, was found to reduce expression of the ADAM10 and ADAM17 inhibitor, TIMP-3, in vitro and in vivo (Amour et al. 1998, 2000; Hoe et al. 2007). TIMP-3 was also reported to decrease surface levels of ADAM10 and APP (Hoe et al. 2007). Interestingly, TIMP-3 protein was increased in 3xTg-AD mice and in human AD brains where a majority of the staining was observed in neurons (Hoe et al. 2007).

Affecting ADAM trafficking is also a way to regulate APP α-secretase cleavage. Synapse-associated protein-97 (SAP97) works as a cargo protein involved in protein trafficking at excitatory synapses. SAP97 and ADAM10 interact and colocalize in hippocampal neurons in punctate spine-like structures. NMDAR activation affects the redistribution of ADAM10/SAP97 within the cell and enhances α-secretase activity. Moreover, interaction between ADAM10 and SAP97 is needed for ADAM10 trafficking to the post-synaptic compartment (Marcello et al. 2007). Utilization of a cell-permeable peptide to interfere with the ADAM10/SAP97 complex in mice can lead to a reduction of ADAM10 in the post-synaptic compartment and to a decrease in sAPPα release. An increase of Aβ production and tau phosphorylation was also observed under these conditions of blockade of ADAM10 synaptic trafficking (Epis et al. 2010).

ADAM10 and ADAM17 were shown to be secreted outside the cells in exosomes (Stoeck et al. 2006). Exosomes, which are small vesicles secreted after fusion of late endosomes to the plasma membrane, are suggested to play a fundamental role in the communication between cells (Fevrier and Raposo 2004). It was shown that ADAM10 in exosomes conserved its constitutive and regulated sheddase activity toward L1 and CD44 (Stoeck et al. 2006). More interestingly, exosomes can be secreted by neurons, and contain APP (Faure et al. 2006; Vingtdeux et al. 2007; Lachenal et al. 2011), indicating that these specific vesicles might be a compartment where α-secretase shedding of APP could also happen.

sAPPα as a neurotrophic and neuroprotective factor

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

Even though the APP ectodomain released by β-secretase, sAPPβ, appears to be neurotoxic (Nikolaev et al. 2009; Vohra et al. 2010), the α-secretase-derived APP ectodomain, sAPPα, has been associated with potent neurotrophic and neuroprotective properties (Mattson et al. 1993; Caille et al. 2004; ). In different models of excitotoxicity or proteasomal stress, sAPPα was found to preserve neuronal integrity and survival (Furukawa et al. 1996a; Furukawa and Mattson 1998; Copanaki et al. 2010). In vivo, brain expression of an APP mutant at the α-secretase site resistant for proteolysis led to severe neurodegeneration and cognitive defects (Moechars et al. 1996). In line with this observation, sAPPα showed memory enhancing properties, when administered intracerebroventricularly in mice (Meziane et al. 1998), and its expression is able to rescue the anatomical, behavioral, and electrophysiological defects triggered by APP deficiency (Ring et al. 2007). Moreover, moderate neuron-specific expression of ADAM10 led to improved long-term potentiation and cognitive performance in V717I-APP transgenic mice, an effect that correlated with an increase in sAPPα secretion and a decrease in Aβ levels and amyloid deposition (Postina et al. 2004; Clement et al. 2008). In addition, decreased CSF sAPPα levels were found in familial and sporadic AD patients (Lannfelt et al. 1995; Sennvik et al. 2000), and correlated with poor memory performance in patients with AD (Almkvist et al. 1997; Fellgiebel et al. 2009). Thus, in vitro and in vivo studies strongly indicate that sAPPα has neuroprotective effects in different models of neuronal stress and is down-regulated during AD.

Some early evidence has also suggested a role for sAPPα as a trophic factor involved, for instance, in cell growth in proliferating cells, in neurite extension in neurons, or in dendritic motility in melanocytes (Saitoh et al. 1989; Jin et al. 1994; Quast et al. 2003). Although the evidence is now strong that sAPPα is neurotrophic and neuroprotective, the mechanisms by which this APP metabolite acts remain elusive. More specifically no definitive specific receptor or cell surface interacting partner has been identified. sAPPα and sAPPβ, which share a large sequence of APP ectodomain, have been proposed to have diametrically opposite effects on neuronal integrity. Indeed, sAPPβ via its binding to the TNF receptor superfamily member, death receptor 6, may cause caspase 6-dependent neuronal death by promoting axonal pruning in vitro and in vivo (Nikolaev et al. 2009; Vohra et al. 2010; Kuester et al. 2011). Consequently, sAPPβ is unable to recapitulate the neuropotective effect of sAPPα against excitotoxicity (Furukawa et al. 1996b). These observations suggest that the heparin-binding domain at the C-terminal end of sAPPα may bear the neuroprotective function of this fragment (Furukawa et al. 1996b). Whether this domain controls sAPPα binding to a hypothetical receptor remains to be determined. Interestingly, a role in the control of APP dimerization by sAPPα has recently been proposed, suggesting that APP itself may represent a receptor for sAPPα (Gralle et al. 2009). The authors also provided evidence that this effect on APP dimerization may control the neuroprotective effect of sAPPα (Gralle et al. 2009). Whether the C-terminal heparin-binding domain of sAPPα is involved in sAPPα/APP interaction remains to be determined.

Conclusion

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References

The introduction into the literature of the term ‘secretase’, coined to refer to a specific family of membrane proteases (Hooper et al. 1987), ushered in a new field of biology that has attracted a lot of interest because of its critical implications in physiology and important ramifications in several diseases, including cancer and AD. One of these ramifications is the therapeutic potential of increasing APP α-secretase cleavage. This approach is seriously pursued because it could potentially be a promising anti-amyloidogenic alternative to the challenging strategies aimed at interfering with β- or γ-secretase activity. Moreover, such a strategy could also lead to neuroprotection via the increased production of the APP metabolite sAPPα. Recent studies have established more firmly that, in neurons, ADAM10 and probably ADAM17 are the genuine constitutive and regulated α-secretases, respectively (Fig. 1). Together with the progress made in our understanding of the physiology of these ADAMs, these studies will help us to determine whether approaches aimed at activating α-secretase by specifically targeting these proteases can be safely implemented in vivo and thus have therapeutic value in AD.

image

Figure 1.  Proposed physiological roles of the main candidates for the constitutive and regulated α-secretase activities. Whereas ADAM10 appears to represent the genuine constitutive α-secretase in neurons, ADAM17 and ADAM9 are likely to be the main regulated α-secretases. The physiological roles of these three proteases listed in this scheme were mainly revealed from the study of the corresponding KO mouse models. This list does not take into account the existence of a large number of substrates for these ADAMs and thus does not include the other relevant biological processes. Also note that additional α-secretase candidates, not listed here, have been proposed for which further evidence is needed (see text for details).

Download figure to PowerPoint

References

  1. Top of page
  2. Abstract
  3. APP α-secretase cleavage
  4. The ADAMs
  5. α-Secretase and ADAM17
  6. α-Secretase and ADAM10
  7. α-Secretase and ADAM9
  8. Comparative contribution to APP α-secretase cleavage by ADAM17, 10, and 9
  9. Other α-secretase candidates
  10. Mechanisms of regulation of APP α-secretase cleavage
  11. sAPPα as a neurotrophic and neuroprotective factor
  12. Conclusion
  13. Acknowledgements
  14. Conflict of interest
  15. References
  • Adlerz L., Holback S., Multhaup G. and Iverfeldt K. (2007) IGF-1-induced processing of the amyloid precursor protein family is mediated by different signaling pathways. J. Biol. Chem. 282, 1020310209.
  • Ahmad M., Takino T., Miyamori H., Yoshizaki T., Furukawa M. and Sato H. (2006) Cleavage of amyloid-beta precursor protein (APP) by membrane-type matrix metalloproteinases. J. Biochem. 139, 517526.
  • Alfa Cisse M., Sunyach C., Slack B. E., Fisher A., Vincent B. and Checler F. (2007) M1 and M3 muscarinic receptors control physiological processing of cellular prion by modulating ADAM17 phosphorylation and activity. J. Neurosci. 27, 40834092.
  • Allinson T. M., Parkin E. T., Condon T. P., Schwager S. L., Sturrock E. D., Turner A. J. and Hooper N. M. (2004) The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein. Eur. J. Biochem. 271, 25392547.
  • Allsop D., Yamamoto T., Kametani F., Miyazaki N. and Ishii T. (1991) Alzheimer amyloid beta/A4 peptide binding sites and a possible ‘APP-secretase’ activity associated with rat brain cortical membranes. Brain Res. 551, 19.
  • Almkvist O., Basun H., Wagner S. L., Rowe B. A., Wahlund L. O. and Lannfelt L. (1997) Cerebrospinal fluid levels of alpha-secretase-cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation. Arch. Neurol. 54, 641644.
  • Amour A., Slocombe P. M., Webster A. et al. (1998) TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett. 435, 3944.
  • Amour A., Knight C. G., Webster A., Slocombe P. M., Stephens P. E., Knauper V., Docherty A. J. and Murphy G. (2000) The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett. 473, 275279.
  • Anders A., Gilbert S., Garten W., Postina R. and Fahrenholz F. (2001) Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases. FASEB J. 15, 18371839.
  • Anderson J. P., Esch F. S., Keim P. S., Sambamurti K., Lieberburg I. and Robakis N. K. (1991) Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells. Neurosci. Lett. 128, 126128.
  • Arikkath J. and Reichardt L. F. (2008) Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity. Trends Neurosci. 31, 487494.
  • Arribas J. and Massague J. (1995) Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism. J. Cell Biol. 128, 433441.
  • Arribas J., Coodly L., Vollmer P., Kishimoto T. K., Rose-John S. and Massague J. (1996) Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease inhibitors. J. Biol. Chem. 271, 1137611382.
  • Asai M., Hattori C., Szabo B., Sasagawa N., Maruyama K., Tanuma S. and Ishiura S. (2003) Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochem. Biophys. Res. Commun. 301, 231235.
  • Baker A. H., Edwards D. R. and Murphy G. (2002) Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J. Cell Sci. 115, 37193727.
  • Baki L., Marambaud P., Efthimiopoulos S. et al. (2001) Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex. Proc. Natl. Acad. Sci. USA 98, 23812386.
  • Bernstein H. G., Bukowska A., Krell D., Bogerts B., Ansorge S. and Lendeckel U. (2003) Comparative localization of ADAMs 10 and 15 in human cerebral cortex normal aging, Alzheimer disease and Down syndrome. J. Neurocytol. 32, 153160.
  • Black R. A., Rauch C. T., Kozlosky C. J. et al. (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729733.
  • Blacker M., Noe M. C., Carty T. J., Goodyer C. G. and LeBlanc A. C. (2002) Effect of tumor necrosis factor-alpha converting enzyme (TACE) and metalloprotease inhibitor on amyloid precursor protein metabolism in human neurons. J. Neurochem. 83, 13491357.
  • Blobel C. P. (2005) ADAMs: key components in EGFR signalling and development. Nat. Rev. Mol. Cell Biol. 6, 3243.
  • Buxbaum J. D., Koo E. H. and Greengard P. (1993) Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. Proc. Natl. Acad. Sci. USA 90, 91959198.
  • Buxbaum J. D., Liu K. N., Luo Y., Slack J. L., Stocking K. L., Peschon J. J., Johnson R. S., Castner B. J., Cerretti D. P. and Black R. A. (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 2776527767.
  • Caccamo A., Oddo S., Billings L. M., Green K. N., Martinez-Coria H., Fisher A. and LaFerla F. M. (2006) M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49, 671682.
  • Caille I., Allinquant B., Dupont E., Bouillot C., Langer A., Muller U. and Prochiantz A. (2004) Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development 131, 21732181.
  • Caporaso G. L., Gandy S. E., Buxbaum J. D., Ramabhadran T. V. and Greengard P. (1992) Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. Proc. Natl. Acad. Sci. USA 89, 30553059.
  • Carey R. M., Blusztajn J. K. and Slack B. E. (2011) Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin. BMC Cell Biol. 12, 20.
  • Checler F. (1995) Processing of the beta-amyloid precursor protein and its regulation in Alzheimer’s disease. J. Neurochem. 65, 14311444.
  • Cisse M. A., Sunyach C., Lefranc-Jullien S., Postina R., Vincent B. and Checler F. (2005) The disintegrin ADAM9 indirectly contributes to the physiological processing of cellular prion by modulating ADAM10 activity. J. Biol. Chem. 280, 4062440631.
  • Cisse M., Braun U., Leitges M., Fisher A., Pages G., Checler F. and Vincent B. (2011a) ERK1-independent alpha-secretase cut of beta-amyloid precursor protein via M1 muscarinic receptors and PKCalpha/epsilon. Mol. Cell. Neurosci. 47, 223232.
  • Cisse M., Duplan E., Guillot-Sestier M. V., Rumigny J., Bauer C., Pages G., Orzechowski H. D., Slack B. E., Checler F. and Vincent B. (2011b) The extracellular regulated kinase-1 (ERK1) controls regulated {alpha}-secretase-mediated processing, promoter transactivation and mRNA levels of the cellular prion protein. J. Biol. Chem. 286, 2919229206.
  • Clement A. B., Hanstein R., Schroder A., Nagel H., Endres K., Fahrenholz F. and Behl C. (2008) Effects of neuron-specific ADAM10 modulation in an in vivo model of acute excitotoxic stress. Neuroscience 152, 459468.
  • Copanaki E., Chang S., Vlachos A., Tschape J. A., Muller U. C., Kogel D. and Deller T. (2010) sAPPalpha antagonizes dendritic degeneration and neuron death triggered by proteasomal stress. Mol. Cell. Neurosci. 44, 386393.
  • Davis-Salinas J., Saporito-Irwin S. M., Donovan F. M., Cunningham D. D. and Van Nostrand W. E. (1994) Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid beta-protein precursor. J. Biol. Chem. 269, 2262322627.
  • De Strooper B. and Annaert W. (2010) Novel research horizons for presenilins and gamma-secretases in cell biology and disease. Annu. Rev. Cell Dev. Biol. 26, 235260.
  • Delarasse C., Auger R., Gonnord P., Fontaine B. and Kanellopoulos J. M. (2011) The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein. J. Biol. Chem. 286, 25962606.
  • Diaz-Rodriguez E., Montero J. C., Esparis-Ogando A., Yuste L. and Pandiella A. (2002) Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding. Mol. Biol. Cell 13, 20312044.
  • Dickson D. W. (2009) Neuropathology of non-Alzheimer degenerative disorders. Int. J. Clin. Exp. Pathol. 3(1), 123.
  • Doedens J. R. and Black R. A. (2000) Stimulation-induced down-regulation of tumor necrosis factor-alpha converting enzyme. J. Biol. Chem. 275, 1459814607.
  • Duyckaerts C., Delatour B. and Potier M. C. (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol. 118, 536.
  • Edwards D. R., Handsley M. M. and Pennington C. J. (2008) The ADAM metalloproteinases. Mol. Aspects Med. 29, 258289.
  • Epis R., Marcello E., Gardoni F. et al. (2010) Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer’s disease. Brain 133, 33233335.
  • Esch F. S., Keim P. S., Beattie E. C., Blacher R. W., Culwell A. R., Oltersdorf T., McClure D. and Ward P. J. (1990) Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248, 11221124.
  • Faure J., Lachenal G., Court M. et al. (2006) Exosomes are released by cultured cortical neurones. Mol. Cell. Neurosci. 31, 642648.
  • Fellgiebel A., Kojro E., Muller M. J., Scheurich A., Schmidt L. G. and Fahrenholz F. (2009) CSF APPs alpha and phosphorylated tau protein levels in mild cognitive impairment and dementia of Alzheimer’s type. J. Geriatr. Psychiatry Neurol. 22, 39.
  • Fevrier B. and Raposo G. (2004) Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr. Opin. Cell Biol. 16, 415421.
  • Furukawa K. and Mattson M. P. (1998) Secreted amyloid precursor protein alpha selectively suppresses N-methyl-D-aspartate currents in hippocampal neurons: involvement of cyclic GMP. Neuroscience 83, 429438.
  • Furukawa K., Barger S. W., Blalock E. M. and Mattson M. P. (1996a) Activation of K+ channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein. Nature 379, 7478.
  • Furukawa K., Sopher B. L., Rydel R. E., Begley J. G., Pham D. G., Martin G. M., Fox M. and Mattson M. P. (1996b) Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J. Neurochem. 67, 18821896.
  • Georgakopoulos A., Marambaud P., Efthimiopoulos S. et al. (1999) Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Mol. Cell 4, 893902.
  • Georgakopoulos A., Litterst C., Ghersi E., Baki L., Xu C., Serban G. and Robakis N. K. (2006) Metalloproteinase/presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J. 25, 12421252.
  • Giulian D., Haverkamp L. J., Yu J., Karshin W., Tom D., Li J., Kazanskaia A., Kirkpatrick J. and Roher A. E. (1998) The HHQK domain of beta-amyloid provides a structural basis for the immunopathology of Alzheimer’s disease. J. Biol. Chem. 273, 2971929726.
  • Golde T. E., Petrucelli L. and Lewis J. (2010) Targeting Abeta and tau in Alzheimer’s disease, an early interim report. Exp. Neurol. 223, 252266.
  • Gralle M., Botelho M. G. and Wouters F. S. (2009) Neuroprotective secreted amyloid precursor protein acts by disrupting amyloid precursor protein dimers. J. Biol. Chem. 284, 1501615025.
  • Hartmann D., de Strooper B., Serneels L. et al. (2002) The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum. Mol. Genet. 112, 26152624.
  • Higashi S. and Miyazaki K. (2003) Novel processing of beta-amyloid precursor protein catalyzed by membrane type 1 matrix metalloproteinase releases a fragment lacking the inhibitor domain against gelatinase A. Biochemistry 422, 65146526.
  • Hoe H. S., Cooper M. J., Burns M. P., Lewis P. A., van der Brug M., Chakraborty G., Cartagena C. M., Pak D. T., Cookson M. R. and Rebeck G. W. (2007) The metalloprotease inhibitor TIMP-3 regulates amyloid precursor protein and apolipoprotein E receptor proteolysis. J. Neurosci. 274, 1089510905.
  • Hooper N. M., Keen J., Pappin D. J. and Turner A. J. (1987) Pig kidney angiotensin converting enzyme. Purification and characterization of amphipathic and hydrophilic forms of the enzyme establishes C-terminal anchorage to the plasma membrane. Biochem. J. 247, 8593.
  • Horiuchi K., Le Gall S., Schulte M., Yamaguchi T., Reiss K., Murphy G., Toyama Y., Hartmann D., Saftig P. and Blobel C. P. (2007) Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. Mol. Biol. Cell 18, 176188.
  • Hung A. Y., Haass C., Nitsch R. M., Qiu W. Q., Citron M., Wurtman R. J., Growdon J. H. and Selkoe D. J. (1993) Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J. Biol. Chem. 268, 2295922962.
  • Hwang E. M., Kim S. K., Sohn J. H., Lee J. Y., Kim Y., Kim Y. S. and Mook-Jung I. (2006) Furin is an endogenous regulator of alpha-secretase associated APP processing. Biochem. Biophys. Res. Commun. 349, 654659.
  • Jacobsen K. T., Adlerz L., Multhaup G. and Iverfeldt K. (2010) Insulin-like growth factor-1 (IGF-1)-induced processing of amyloid-beta precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases. J. Biol. Chem. 285, 1022310231.
  • Janes P. W., Saha N., Barton W. A., Kolev M. V., Wimmer-Kleikamp S. H., Nievergall E., Blobel C. P., Himanen J. P., Lackmann M. and Nikolov D. B. (2005) Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 123, 291304.
  • Jin L. W., Ninomiya H., Roch J. M., Schubert D., Masliah E., Otero D. A. and Saitoh T. (1994) Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J. Neurosci. 14, 54615470.
  • Jorissen E., Prox J., Bernreuther C. et al. (2010) The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J. Neurosci. 301, 48334844.
  • Kamenetz F., Tomita T., Hsieh H., Seabrook G., Borchelt D., Iwatsubo T., Sisodia S. and Malinow R. (2003) APP processing and synaptic function. Neuron 37, 925937.
  • Karkkainen I., Rybnikova E., Pelto-Huikko M. and Huovila A. P. (2000) Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. Mol. Cell. Neurosci. 15, 547560.
  • Killock D. J. and Ivetic A. (2010) The cytoplasmic domains of TNFalpha-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding. Biochem. J. 428, 293304.
  • Kim M. L., Zhang B., Mills I. P., Milla M. E., Brunden K. R. and Lee V. M. (2008) Effects of TNFalpha-converting enzyme inhibition on amyloid beta production and APP processing in vitro and in vivo. J. Neurosci. 284, 1205212061.
  • Koike H., Tomioka S., Sorimachi H., Saido T. C., Maruyama K., Okuyama A., Fujisawa-Sehara A., Ohno S., Suzuki K. and Ishiura S. (1999) Membrane-anchored metalloprotease MDC9 has an alpha-secretase activity responsible for processing the amyloid precursor protein. Biochem. J. 343, 371375.
  • Kojro E., Gimpl G., Lammich S., Marz W. and Fahrenholz F. (2001) Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10. Proc. Natl. Acad. Sci. USA 981, 58155820.
  • Kojro E., Postina R., Buro C., Meiringer C., Gehrig-Burger K. and Fahrenholz F. (2006) The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB J. 20, 512514.
  • Komano H., Seeger M., Gandy S., Wang G. T., Krafft G. A. and Fuller R. S. (1998) Involvement of cell surface glycosyl-phosphatidylinositol-linked aspartyl proteases in alpha-secretase-type cleavage and ectodomain solubilization of human Alzheimer beta-amyloid precursor protein in yeast. J. Biol. Chem. 273, 3164831651.
  • Kopan R. and Ilagan M. X. (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216233.
  • Kuester M., Kemmerzehl S., Dahms S. O., Roeser D. and Than M. E. (2011) The crystal structure of death receptor 6 (DR6): a potential receptor of the amyloid precursor protein (APP). J. Mol. Biol. 409, 189201.
  • Kuhn P. H., Wang H., Dislich B., Colombo A., Zeitschel U., Ellwart J. W., Kremmer E., Rossner S. and Lichtenthaler S. F. (2010) ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 291, 30203032.
  • La Marca R., Cerri F., Horiuchi K., Bachi A., Feltri M. L., Wrabetz L., Blobel C. P., Quattrini A., Salzer J. L. and Taveggia C. (2011) TACE (ADAM17) inhibits Schwann cell myelination. Nat. Neurosci. 14, 857865.
  • Lachenal G., Pernet-Gallay K., Chivet M., Hemming F. J., Belly A., Bodon G., Blot B., Haase G., Goldberg Y. and Sadoul R. (2011) Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol. Cell. Neurosci. 46, 409418.
  • Lambert J. C. and Amouyel P. (2007) Genetic heterogeneity of Alzheimer’s disease: complexity and advances. Psychoneuroendocrinology 32, S62S70.
  • Lammich S., Kojro E., Postina R., Gilbert S., Pfeiffer R., Jasionowski M., Haass C. and Fahrenholz F. (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. USA 96, 39223927.
  • Lannfelt L., Basun H., Wahlund L. O., Rowe B. A. and Wagner S. L. (1995) Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer’s disease. Nat. Med. 1, 829832.
  • Lee R. K., Wurtman R. J., Cox A. J. and Nitsch R. M. (1995) Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. Proc. Natl. Acad. Sci. USA 921, 80838087.
  • Lichtenthaler S. F. (2011) Alpha-secretase in Alzheimer’s disease: molecular identity, regulation and therapeutic potential. J. Neurochem. 116, 1021.
  • Lopez-Perez E., Seidah N. G. and Checler F. (1999) Proprotein convertase activity contributes to the processing of the Alzheimer’s beta-amyloid precursor protein in human cells: evidence for a role of the prohormone convertase PC7 in the constitutive alpha-secretase pathway. J. Neurochem. 73, 20562062.
  • Lopez-Perez E., Zhang Y., Frank S. J., Creemers J., Seidah N. and Checler F. (2001) Constitutive alpha-secretase cleavage of the beta-amyloid precursor protein in the furin-deficient LoVo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10. J. Neurochem. 76, 15321539.
  • Malinverno M., Carta M., Epis R., Marcello E., Verpelli C., Cattabeni F., Sala C., Mulle C., Di Luca M. and Gardoni F. (2010) Synaptic localization and activity of ADAM10 regulate excitatory synapses through N-cadherin cleavage. J. Neurosci. 304, 1634316355.
  • Marambaud P. and Robakis N. K. (2005) Genetic and molecular aspects of Alzheimer’s disease shed light on new mechanisms of transcriptional regulation. Genes Brain Behav. 4, 134146.
  • Marambaud P., Chevallier N., Barelli H., Wilk S. and Checler F. (1997) Proteasome contributes to the alpha-secretase pathway of amyloid precursor protein in human cells. J. Neurochem. 68, 698703.
  • Marambaud P., Shioi J., Serban G. et al. (2002) A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21, 19481956.
  • Marambaud P., Wen P. H., Dutt A., Shioi J., Takashima A., Siman R. and Robakis N. K. (2003) A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114, 635645.
  • Marcello E., Gardoni F., Mauceri D. et al. (2007) Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. J. Neurosci. 27, 16821691.
  • Marcinkiewicz M. and Seidah N. G. (2000) Coordinated expression of beta-amyloid precursor protein and the putative beta-secretase BACE and alpha-secretase ADAM10 in mouse and human brain. J. Neurochem. 75, 21332143.
  • Maretzky T., Reiss K., Ludwig A., Buchholz J., Scholz F., Proksch E., de Strooper B., Hartmann D. and Saftig P. (2005a) ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc. Natl. Acad. Sci. USA 102, 91829187.
  • Maretzky T., Schulte M., Ludwig A., Rose-John S., Blobel C., Hartmann D., Altevogt P., Saftig P. and Reiss K. (2005b) L1 is sequentially processed by two differently activated metalloproteases and presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol. Cell. Biol. 252, 90409053.
  • Mattson M. P., Cheng B., Culwell A. R., Esch F. S., Lieberburg I. and Rydel R. E. (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 10, 243254.
  • McDermott J. R. and Gibson A. M. (1991) The processing of Alzheimer A4/beta-amyloid protein precursor: identification of a human brain metallopeptidase which cleaves -Lys-Leu- in a model peptide. Biochem. Biophys. Res. Commun. 179, 11481154.
  • Merlos-Suarez A., Fernandez-Larrea J., Reddy P., Baselga J. and Arribas J. (1998) Pro-tumor necrosis factor-alpha processing activity is tightly controlled by a component that does not affect notch processing. J. Biol. Chem. 273, 2495524962.
  • Meziane H., Dodart J. C., Mathis C., Little S., Clemens J., Paul S. M. and Ungerer A. (1998) Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc. Natl. Acad. Sci. USA 952, 1268312688.
  • Moechars D., Lorent K., De Strooper B., Dewachter I. and Van Leuven F. (1996) Expression in brain of amyloid precursor protein mutated in the alpha-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice. EMBO J. 15, 12651274.
  • Moss M. L., Jin S. L., Milla M. E. et al. (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385, 733736.
  • Muraguchi T., Takegami Y., Ohtsuka T. et al. (2007) RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat. Neurosci. 10, 838845.
  • Naus S., Reipschlager S., Wildeboer D., Lichtenthaler S. F., Mitterreiter S., Guan Z., Moss M. L. and Bartsch J. W. (2006) Identification of candidate substrates for ectodomain shedding by the metalloprotease-disintegrin ADAM8. Biol. Chem. 387, 337346.
  • Nelson W. J. (2008) Regulation of cell–cell adhesion by the cadherin–catenin complex. Biochem. Soc. Trans. 36, 149155.
  • Nikolaev A., McLaughlin T., O’Leary D. D. and Tessier-Lavigne M. (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981989.
  • Nitsch R. M., Slack B. E., Wurtman R. J. and Growdon J. H. (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258, 304307.
  • Nitsch R. M., Kim C. and Growdon J. H. (1998) Vasopressin and bradykinin regulate secretory processing of the amyloid protein precursor of Alzheimer’s disease. Neurochem. Res. 23, 807814.
  • Pan D. and Rubin G. M. (1997) Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 90, 271280.
  • Parkin E. and Harris B. (2009) A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10. J. Neurochem. 108, 14641479.
  • Pastor P. and Goate A. M. (2004) Molecular genetics of Alzheimer’s disease. Curr. Psychiatry Rep. 6, 125133.
  • Postina R., Schroeder A., Dewachter I. et al. (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 113, 14561464.
  • Quast T., Wehner S., Kirfel G., Jaeger K., De Luca M. and Herzog V. (2003) sAPP as a regulator of dendrite motility and melanin release in epidermal melanocytes and melanoma cells. FASEB J. 171, 17391741.
  • Refolo L. M., Salton S. R., Anderson J. P., Mehta P. and Robakis N. K. (1989) Nerve and epidermal growth factors induce the release of the Alzheimer amyloid precursor from PC 12 cell cultures. Biochem. Biophys. Res. Commun. 164, 664670.
  • Reiss K., Maretzky T., Ludwig A., Tousseyn T., de Strooper B., Hartmann D. and Saftig P. (2005) ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling. EMBO J. 24, 742752.
  • Ring S., Weyer S. W., Kilian S. B. et al. (2007) The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J. Neurosci. 272, 78177826.
  • Roberts S. B., Ripellino J. A., Ingalls K. M., Robakis N. K. and Felsenstein K. M. (1994) Non-amyloidogenic cleavage of the beta-amyloid precursor protein by an integral membrane metalloendopeptidase. J. Biol. Chem. 269, 31113116.
  • Roghani M., Becherer J. D., Moss M. L., Atherton R. E., Erdjument-Bromage H., Arribas J., Blackburn R. K., Weskamp G., Tempst P. and Blobel C. P. (1999) Metalloprotease-disintegrin MDC9: intracellular maturation and catalytic activity. J. Biol. Chem. 274, 35313540.
  • Rooke J., Pan D., Xu T. and Rubin G. M. (1996) KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science 273, 12271231.
  • Sahin U., Weskamp G., Kelly K., Zhou H. M., Higashiyama S., Peschon J., Hartmann D., Saftig P. and Blobel C. P. (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J. Cell Biol. 164, 769779.
  • Saitoh T., Sundsmo M., Roch J. M., Kimura N., Cole G., Schubert D., Oltersdorf T. and Schenk D. B. (1989) Secreted form of amyloid beta protein precursor is involved in the growth regulation of fibroblasts. Cell 58, 615622.
  • Sambamurti K., Sevlever D., Koothan T. et al. (1999) Glycosylphosphatidylinositol-anchored proteins play an important role in the biogenesis of the Alzheimer’s amyloid beta-protein. J. Biol. Chem. 274, 2681026814.
  • Selkoe D. J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741766.
  • Sennvik K., Fastbom J., Blomberg M., Wahlund L. O., Winblad B. and Benedikz E. (2000) Levels of alpha- and beta-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimer’s disease patients. Neurosci. Lett. 278, 169172.
  • Sisodia S. S. (1992) Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc. Natl. Acad. Sci. USA 891, 60756079.
  • Six E., Ndiaye D., Laabi Y., Brou C., Gupta-Rossi N., Israel A. and Logeat F. (2003) The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. Proc. Natl. Acad. Sci. USA 100, 76387643.
  • Skovronsky D. M., Fath S., Lee V. M. and Milla M. E. (2001) Neuronal localization of the TNFalpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques. J. Neurobiol. 49, 4046.
  • Slack B. E., Ma L. K. and Seah C. C. (2001) Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme. Biochem. J. 357, 787794.
  • Soond S. M., Everson B., Riches D. W. and Murphy G. (2005) ERK-mediated phosphorylation of Thr735 in TNFalpha-converting enzyme and its potential role in TACE protein trafficking. J. Cell Sci. 118, 23712380.
  • Srinivasan B., Wang Z., Brun-Zinkernagel A. M., Collier R. J., Black R. A., Frank S. J., Barker P. A. and Roque R. S. (2007) Photic injury promotes cleavage of p75NTR by TACE and nuclear trafficking of the p75 intracellular domain. Mol. Cell. Neurosci. 36, 449461.
  • Srour N., Lebel A., McMahon S., Fournier I., Fugere M., Day R. and Dubois C. M. (2003) TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity. FEBS Lett. 554, 275283.
  • Stoeck A., Keller S., Riedle S., Sanderson M. P., Runz S., Le Naour F., Gutwein P., Ludwig A., Rubinstein E. and Altevogt P. (2006) A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44. Biochem. J. 393(Pt 3), 609618.
  • Tachida Y., Nakagawa K., Saito T. et al. (2008) Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production. J. Neurochem. 104, 13871393.
  • Talamagas A. A., Efthimiopoulos S., Tsilibary E. C., Figueiredo-Pereira M. E. and Tzinia A. K. (2007) Abeta(1-40)-induced secretion of matrix metalloproteinase-9 results in sAPPalpha release by association with cell surface APP. Neurobiol. Dis. 28, 304315.
  • Tanabe C., Hotoda N., Sasagawa N., Sehara-Fujisawa A., Maruyama K. and Ishiura S. (2007) ADAM19 is tightly associated with constitutive Alzheimer’s disease APP alpha-secretase in A172 cells. Biochem. Biophys. Res. Commun. 352, 111117.
  • van Tetering G., van Diest P., Verlaan I., van der Wall E., Kopan R. and Vooijs M. (2009) Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. J. Biol. Chem. 284, 3101831027.
  • Tousseyn T., Thathiah A., Jorissen E. et al. (2009) ADAM10, the rate-limiting protease of regulated intramembrane proteolysis of Notch and other proteins, is processed by ADAMS-9, ADAMS-15, and the gamma-secretase. J. Biol. Chem. 284, 1173811747.
  • Uemura K., Kihara T., Kuzuya A., Okawa K., Nishimoto T., Ninomiya H., Sugimoto H., Kinoshita A. and Shimohama S. (2006) Characterization of sequential N-cadherin cleavage by ADAM10 and PS1. Neurosci. Lett. 402, 278283.
  • Vaisar T., Kassim S. Y., Gomez I. G., Green P. S., Hargarten S., Gough P. J., Parks W. C., Wilson C. L., Raines E. W. and Heinecke J. W. (2009) MMP-9 sheds the beta2 integrin subunit (CD18) from macrophages. Mol. Cell Proteomics 8, 10441060.
  • Vincent B. and Checler F. (2011) alpha-Secretase in Alzheimer’s disease and beyond: mechanistic, regulation and function in the shedding of membrane proteins. Curr. Alzheimer Res. [Epub ahead of print].
  • Vingtdeux V., Hamdane M., Loyens A. et al. (2007) Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J. Biol. Chem. 282, 1819718205.
  • Vohra B. P., Sasaki Y., Miller B. R., Chang J., DiAntonio A. and Milbrandt J. (2010) Amyloid precursor protein cleavage-dependent and -independent axonal degeneration programs share a common nicotinamide mononucleotide adenylyltransferase 1-sensitive pathway. J. Neurosci. 304, 1372913738.
  • Walsh D. M. and Selkoe D. J. (2007) A beta oligomers – a decade of discovery. J. Neurochem. 101, 11721184.
  • Wang R., Meschia J. F., Cotter R. J. and Sisodia S. S. (1991) Secretion of the beta/A4 amyloid precursor protein. Identification of a cleavage site in cultured mammalian cells. J. Biol. Chem. 266, 1696016964.
  • Weskamp G., Cai H., Brodie T. A., Higashyama S., Manova K., Ludwig T. and Blobel C. P. (2002) Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life. Mol. Cell. Biol. 22, 15371544.