title: Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease.
abstract: 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.
authors.affiliation: Università degli Studi di Milano, Dipartimento di Scienze Farmacologiche e Biomolecolari and Centre of Excellence on Neurodegenerative Diseases, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Marcello
authors.forename: Claudia
authors.initials: C
authors.lastname: Saraceno
authors.forename: Stefano
authors.initials: S
authors.lastname: Musardo
authors.forename: Hugo
authors.initials: H
authors.lastname: Vara
authors.forename: Alerie Guzman
authors.initials: AG
authors.lastname: de la Fuente
authors.forename: Silvia
authors.initials: S
authors.lastname: Pelucchi
authors.forename: Daniele
authors.initials: D
authors.lastname: Di Marino
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.forename: Isabel
authors.initials: I
authors.lastname: Pérez-Otaño
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Giustetto
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology; D002522:Chlorocebus aethiops; D000074288:Discs Large Homolog 1 Protein; D004705:Endocytosis; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D021381:Protein Transport; D013569:Synapses / Q000201:enzymology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human