Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease.

Elena Marcello (1) , Claudia Saraceno (1) , Stefano Musardo (1) , Hugo Vara (2) , Alerie Guzman de La Fuente (1) , Silvia Pelucchi (1) , Daniele Di Marino (3) , Barbara Borroni (4) , Anna Tramontano (3, 5) , Isabel Pérez-Otaño (6) , Alessandro Padovani (4) , Maurizio Giustetto (2) , Fabrizio Gardoni (1) , Monica Di Luca (1)

1 Dipartimento di Scienze Farmacologiche e Biomolecolari
2 Dipartimento di Neuroscienza
3 Dipartimento di Fisica [Roma La Sapienza]
4 Dipartimento di Scienze Neurologiche
5 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti
6 Centro de Investigaciòn Mèdica Aplicada

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.

Domains: Biochemistry, Molecular Biology; Neuroscience

Elena Marcello, Claudia Saraceno, Stefano Musardo, Hugo Vara, Alerie Guzman de La Fuente, et al.. Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease.. Journal of Clinical Investigation, 2013, 123 (6), pp.2523-38. ⟨10.1172/JCI65401⟩. ⟨pasteur-01054137⟩