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

Marcello, Elena; Saraceno, Claudia; Musardo, Stefano; Vara, Hugo; Fuente, Alerie Guzman de la; Pelucchi, Silvia; Marino, Daniele Di; Borroni, Barbara; Tramontano, Anna; Pérez‐Otaño, Isabel; Padovani, Alessandro; Giustetto, Maurizio; Gardoni, Fabrizio; Luca, Mónica Di

doi:10.1172/jci65401

Cited by 100 publications

(94 citation statements)

References 68 publications

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“…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.…”

mentioning

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.

120

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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mentioning

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.

120

119

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“…In particular, we have identified an atypical AP2-binding motif in the ADAM10 C terminus, which is necessary for AP2 binding and ADAM10 internalization [14]. The lack of AP2 interaction significantly affects ADAM10 synaptic membrane levels, underlying the relevance of clathrin-mediated endocytosis in the modulation of ADAM10 surface expression.…”

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confidence: 99%

ADAM10 in Synaptic Physiology and Pathology

et al. 2013

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Background: Generation of amyloid-β peptide is at the beginning of a cascade that leads to Alzheimer's disease. Amyloid precursor protein (APP) as well as β- and γ-secretases are the principal players involved in amyloid-β (Aβ) production, while α-secretase cleavage on APP prevents Aβ deposition. A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to act as α-secretase in neurons. Objective: Although localization of ADAM10 in the synaptic membrane is the key for its shedding activity, currently, very little is known about the mechanisms that control the synaptic abundance of ADAM10. Results: Two established forms of long-term activity-dependent plasticity, i.e. long-term potentiation and long-term depression (LTD), differentially regulate the synaptic availability and activity of ADAM10. Long-term potentiation decreases ADAM10 surface levels and activity by promoting its endocytosis. This process is mediated by activity-regulated association of ADAM10 with the clathrin adaptor protein 2 (AP2) complex. Conversely, LTD fosters ADAM10 insertion in the membrane and stimulates its activity. Furthermore, ADAM10 interaction with synapse-associated protein 97 (SAP97) is necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced spine morphology changes. Conclusions: Regulated interaction of ADAM10 with SAP97 and AP2 discloses a novel physiological mechanism of ADAM10 activity regulation at the synapses. This phenomenon produces a situation whereby synaptically regulated ADAM10 activity is positioned to modulate synaptic functioning.

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“…The samples were centrifuged in SW-bucket rotor at 60,000g for 90 min. According to the data of electron microscopy, highly purified synaptosomes were present in the layers 1.0 and 1.2 M. Collected portions were diluted ten times with Medium 1 and centrifuged in an fixed-angle rotor at 20,000g for APP within the Aβ domain, thus preventing generation of toxic Aβ peptide and therefore preventing Alzheimer disease [4,5].…”

Section: Isolation and Purification Of Synaptosomesmentioning

confidence: 99%

“…Compositionally simple peptides formed of five times repeated amino acid pairs (Lys-Phe) 5 and (Arg-Ala) 5 were incubated with purified axonal endings (synaptosomes) at 37 °C for 30 min (see "Materials and Methods"). Portions of the reaction medium (15 µl) were analyzed by TLC.…”

Section: Synaptosomes Possess Dipeptidase But Not Carnosinase Activitymentioning

confidence: 99%

“…4a, peak fractions 2, 3, 9, 14, 18) and aminopeptidase NEEMP2 (Fig. 4b, peak fractions 5, 6) are No, the spot of entire peptide is similar to the spot of the peptide alone (no degradation); +, the spot of entire peptide is somewhat weaker; ++, the spot of entire peptide is much weaker; +++, the spot of entire peptide is absent a Evaluation of efficiency of certain substances as NEMP3 activators is based on the TLC data showing the degree of peptide (Lys-Phe) 5 degradation. The developed by ningidrine spots of entire (nondegraded) peptide after overnight incubation with NEMP3 in the presence of a certain substance form test-peptides belong to these "activators".…”

Section: Nemps Separation and Characterizationmentioning

confidence: 99%

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A Group of Weakly Bound to Neurons Extracellular Metallopeptidases (NEMPs)

Kropotova

Mosevitsky

2016

Neurochem Res

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We have found that isolated from mammalian brain (rat, bovine) axonal endings (synaptosomes) degrade peptides of different composition. With the use of low concentration of non ionic detergent Triton X-100 (0.05-0.1 %) four low specific metallopeptidases were detached from synaptosomes. These peptidases were named Neuronal EctoMetalloPeptidases (NEMPs). Using specially designed test-peptides they were characterized as: carboxypeptidase (NEMP1), aminopeptidase (NEMP2) and endopeptidases NEMP3 and NEMP4. NEMPs are true peptidases (oligopeptidases), because they are able efficiently degrade peptides containing less than 40 amino acid residues. Specific properties of some NEMPs were revealed. NEMP1 is a small protein (molecular mass of about 10 kDa), which tends to dynamic oligomerization. NEMP3 needs activation. Some amino acids activate this enzyme. As far as we know, these properties were not ascribed to the known similarly localized peptidases. A possible physiological function of low specific NEMPs is participation in control of wide range of neuropeptides secreted in the synaptic cleft. However, NEMPs also due to their low specificity can destroy introduced in brain therapeutic peptides. The data obtained in this study open new opportunities for the protection of synthetic therapeutic peptides in brain and, possibly, in other tissues.

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

Cited by 100 publications

References 68 publications

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

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

ADAM10 in Synaptic Physiology and Pathology

A Group of Weakly Bound to Neurons Extracellular Metallopeptidases (NEMPs)

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