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.
Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease / E. Marcello, C. Saraceno, S. Musardo, H. Vara, A.G. de la Fuente, S. Pelucchi, D. Di Marino, B. Borroni, A. Tramontano, I. Pérez-Otaño, A. Padovani, M. Giustetto, F. Gardoni, M. Di Luca. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 123:6(2013 Jun 03), pp. 2523-2538.
|Titolo:||Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease|
MARCELLO, ELENA (Primo)
MUSARDO, STEFANO (Secondo)
GARDONI, FABRIZIO (Penultimo)
|Parole Chiave:||Endocytosis ; Neuronal Plasticity ; ADAM Proteins ; Adaptor Proteins, Signal Transducing ; Alzheimer Disease ; Amino Acid Motifs ; Amino Acid Sequence ; Amyloid Precursor Protein Secretases ; Amyloid beta-Protein Precursor ; Animals ; COS Cells ; Cell Membrane ; Cercopithecus aethiops ; Fatty Acid-Binding Proteins ; Hippocampus ; Humans ; Long-Term Potentiation ; Long-Term Synaptic Depression ; Membrane Proteins ; Mice; Models, Molecular; Molecular Sequence Data ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping ; Protein Transport ; Synapses|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore BIO/10 - Biochimica
|Data di pubblicazione:||3-giu-2013|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1172/JCI65401|
|Appare nelle tipologie:||01 - Articolo su periodico|