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

• Published in: The Journal of clinical investigation Vol. 123; no. 6; pp. 2523 - 2538
• Main Authors: Marcello, Elena, Saraceno, Claudia, Musardo, Stefano, Vara, Hugo, de la Fuente, Alerie Guzman, Pelucchi, Silvia, Di Marino, Daniele, Borroni, Barbara, Tramontano, Anna, Pérez-Otaño, Isabel, Padovani, Alessandro, Giustetto, Maurizio, Gardoni, Fabrizio, Di Luca, Monica
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2013
• Subjects: ADAM Proteins; ADAM Proteins - chemistry; ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAM10 Protein; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Signal Transducing - metabolism; Alzheimer Disease; Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Alzheimer's disease; Amino Acid Motifs; Amino Acid Sequence; Amyloid beta-Protein Precursor; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Biochemistry, Molecular Biology; Biomedical research; Cell Membrane; Cell Membrane - enzymology; Cercopithecus aethiops; Cognitive science; COS Cells; Development and progression; Endocytosis; Experiments; Fatty Acid-Binding Proteins; Fatty Acid-Binding Proteins - chemistry; Fatty Acid-Binding Proteins - metabolism; Genetic aspects; Hippocampus; Hippocampus - enzymology; Humans; Life Sciences; Long-Term Potentiation; Long-Term Synaptic Depression; Membrane Proteins; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metalloenzymes; Mice; Models, Molecular; Molecular Sequence Data; Neuronal Plasticity; Neuroplasticity; Neuroscience; Physiological aspects; Protein Binding; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Protein Transport; Proteins; Software; Synapses; Synapses - enzymology; Italy; Spain
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci65401

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.