Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer’s disease

Epis, Roberta; Marcello, Elena; Gardoni, Fabrizio; Vastagh, Csaba; Malinverno, Matteo; Balducci, Claudia; Colombo, Alessio; Borroni, Barbara; Vara, Hugo; Dell’Agli, Mario; Cattabeni, F.; Giustetto, Maurizio; Borsello, Tiziana; Forloni, Gianluigi; Padovani, Alessandro; Luca, Monica Di

doi:10.1093/brain/awq217

Cited by 67 publications

(46 citation statements)

References 52 publications

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“…The interaction involves the SH3 domain of SAP97 and an atypical proline-rich domain within the C-terminal region of ADAM10, and favours the forward trafficking of ADAM10 and its localization in synaptic membranes and, thereby, its APP-cleaving activity (12). The ADAM10/SAP97 interaction has been shown to be reduced in brains from AD patients (15), and the disruption of the association between SAP97 and ADAM10 in vivo using peptides leads to the generation of a nontransgenic model of the disease (16). Thus, forward trafficking and membrane insertion are crucial not only for maintaining a pool of ADAM10 at synaptic sites and for ADAM10-shedding activity, but also for healthy neuronal function.…”

Section: Introductionmentioning

confidence: 99%

Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease

Marcello¹,

Saraceno²,

Musardo³

et al. 2013

J. Clin. Invest.

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100

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A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit β-amyloid peptide (Aβ) formation in Alzheimer's disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease

Marcello¹,

Saraceno²,

Musardo³

et al. 2013

J. Clin. Invest.

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100

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“…Among them, ADAM10 is the primary endogenous ␣-secretase (Jorissen et al, 2010;Kuhn et al, 2010). Evidence from both AD mouse models and AD human patients suggests the involvement of ADAM10 in the regulation of AD pathogenesis (Epis et al, 2010;Kim et al, 2010). In addition to APP processing, ADAM10 is involved in the shedding of many other biologically important proteins (e.g., Notch, N-cadherin, and Nectin-1) from cell membranes (Hartmann et al, 2002;Uemura et al, 2007;Kim et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The activity of ADAM10 is regulated by NMDA receptors (NMDARs), which modulate synaptic trafficking of ADAM10 via synapse-associated protein-97 (SAP97) (Marcello et al, 2007). Interference of the interaction between ADAM10 and SAP97 causes sporadic AD (Epis et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Activation of NMDA Receptors Upregulates A Disintegrin and Metalloproteinase 10 via a Wnt/MAPK Signaling Pathway

Wan

Li³

et al. 2012

J. Neurosci.

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A disintegrin and metalloproteinase 10 (ADAM10) is the constitutive ␣-secretase that governs the nonamyloidogenic pathway of ␤-amyloid precursor protein processing and is an attractive drug target for treating Alzheimer's disease. To date, little is known about the mechanism by which ADAM10 is regulated in neurons. Using mouse primary cortical neurons, we show here that NMDA receptor (NMDAR) activation led to upregulation of the genes encoding ADAM10 and ␤-catenin proteins. Interestingly, the ADAM10 upregulation was abolished by inhibitors of Wnt/␤-catenin signaling. Conversely, activation of the Wnt/␤-catenin signaling pathway by recombinant Wnt3a stimulated ADAM10 expression. We further showed that both the NMDAR-and Wnt3a-induced ADAM10 upregulation was blocked by ERK inhibitors. We suggest that the NMDARs control ADAM10 expression via a Wnt/MAPK signaling pathway.

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“…However, ADAM10 has emerged as the constitutive and inducible APP α-secretase in neurons (5). Of note, ADAM9 and ADAM17 do not recover α-secretase proteolysis of APP in the absence of ADAM10 (5), neuron-specific overexpression of ADAM10 decreases Aβ load in a mouse model of AD (6), and impaired ADAM10 trafficking to the synapse generates a model of sporadic AD (7). Similarly, human studies have observed deficits in ADAM10 expression (8), trafficking (9), and activity (10) in AD.…”

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confidence: 99%

Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP

Corbett

Gonzalez

Pahan

2015

Proc. Natl. Acad. Sci. U.S.A.

124

119

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Amyloid precursor protein (APP) derivative β-amyloid (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). Sequential proteolysis of APP by β-secretase and γ-secretase generates Aβ. Conversely, the α-secretase "a disintegrin and metalloproteinase" 10 (ADAM10) cleaves APP within the eventual Aβ sequence and precludes Aβ generation. Therefore, up-regulation of ADAM10 represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid metabolism. Here, we determined that the Adam10 promoter harbors PPAR response elements; that knockdown of PPARα, but not PPARβ or PPARγ, decreases the expression of Adam10; and that lentiviral overexpression of PPARα restored ADAM10 expression in Ppara −/− neurons. Gemfibrozil, an agonist of PPARα, induced the recruitment of PPARα:retinoid x receptor α, but not PPARγ coactivator 1α (PGC1α), to the Adam10 promoter in wild-type mouse hippocampal neurons and shifted APP processing toward the α-secretase, as determined by augmented soluble APPα and decreased Aβ production. Accordingly, Ppara −/− mice displayed elevated SDS-stable, endogenous Aβ and Aβ 1-42 relative to wild-type littermates, whereas 5XFAD mice null for PPARα (5X/α −/− ) exhibited greater cerebral Aβ load relative to 5XFAD littermates. These results identify PPARα as an important factor regulating neuronal ADAM10 expression and, thus, α-secretase proteolysis of APP.is the most prevalent neurodegenerative disease. Although the precise physiologic changes that trigger development of AD remain unknown, abnormal metabolism of the type 1 transmembrane amyloid precursor protein (APP) into amyloid-β (Aβ) plays a causative role in AD (1). Sequential proteolytic processing of APP by the aspartic proteases β-secretase 1 (BACE1) and γ-secretase (reviewed in ref.2) at ectodomain and intramembrane sites, respectively, generates pathogenic Aβ fragments between residues 36 and 43. Conversely, juxtamembrane cleavage of APP between K16/L17 residues by α-secretase precludes Aβ generation and results in clearance of APP (3).Several proteases have been suggested as AD-relevant α-secretases, many of which belong to the "a disintegrin and metalloproteinase" (ADAM) Zn 2+ sheddase family (reviewed in ref. 4) and include ADAM9, ADAM10, and ADAM17. However, ADAM10 has emerged as the constitutive and inducible APP α-secretase in neurons (5). Of note, ADAM9 and ADAM17 do not recover α-secretase proteolysis of APP in the absence of ADAM10 (5), neuron-specific overexpression of ADAM10 decreases Aβ load in a mouse model of AD (6), and impaired ADAM10 trafficking to the synapse generates a model of sporadic AD (7). Similarly, human studies have observed deficits in ADAM10 expression (8), trafficking (9), and activity (10) in AD. Therefore, dysregulation of ADAM10 may play a significant role in the establishment of Aβ pathology. However, little is known about the genetic regulation of ADAM10....

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Blocking ADAM10 synaptic trafficking generates a model of sporadic Alzheimer’s disease

Cited by 67 publications

References 52 publications

Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease

Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease

Activation of NMDA Receptors Upregulates A Disintegrin and Metalloproteinase 10 via a Wnt/MAPK Signaling Pathway

Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP

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