%0 Journal Article %T Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease. %+ Dipartimento di Scienze Farmacologiche e Biomolecolari %+ Dipartimento di Neuroscienza %+ Dipartimento di Fisica [Roma La Sapienza] %+ Dipartimento di Scienze Neurologiche %+ Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti %+ Centro de Investigaciòn Mèdica Aplicada %A Marcello, Elena %A Saraceno, Claudia %A Musardo, Stefano %A Vara, Hugo %A de La Fuente, Alerie Guzman %A Pelucchi, Silvia %A Di Marino, Daniele %A Borroni, Barbara %A Tramontano, Anna %A Pérez-Otaño, Isabel %A Padovani, Alessandro %A Giustetto, Maurizio %A Gardoni, Fabrizio %A Di Luca, Monica %Z This work was supported by funding from the European Union’s Seventh Framework Program (FP7 2007-2013) under Grant Agreement no. PIAP-GA-2008-217902 to M. Di Luca, from Fondazione CARIPLO (project number 2319-2008) to M. Di Luca, from FIRB-Accordi di Programma, project code RBAP11HSZS to M. Di Luca, from PRIN 2010-2011 2010PWNJXK to M. Di Luca, from the Italian Institute of Technology SEED project to A. Tramontano. %< avec comité de lecture %@ 0021-9738 %J Journal of Clinical Investigation %I American Society for Clinical Investigation %V 123 %N 6 %P 2523-38 %8 2013-05-31 %D 2013 %R 10.1172/JCI65401 %M 23676497 %Z Life Sciences [q-bio]/Biochemistry, Molecular Biology %Z Cognitive science/NeuroscienceJournal articles %X 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. %G English %2 https://riip.hal.science/pasteur-01054137/document %2 https://riip.hal.science/pasteur-01054137/file/Marcello_et_al.pdf %L pasteur-01054137 %U https://riip.hal.science/pasteur-01054137 %~ RIIP %~ RIIP_FCB