Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer’s disease
Elena Marcello, … , Fabrizio Gardoni, Monica Di Luca
Elena Marcello, … , Fabrizio Gardoni, Monica Di Luca
Published May 8, 2013
Citation Information: J Clin Invest. 2013;123(6):2523-2538. https://doi.org/10.1172/JCI65401.
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Research Article Neuroscience

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

Elena Marcello, Claudia Saraceno, Stefano Musardo, Hugo Vara, Alerie Guzman de la Fuente, Silvia Pelucchi, Daniele Di Marino, Barbara Borroni, Anna Tramontano, Isabel Pérez-Otaño, Alessandro Padovani, Maurizio Giustetto, Fabrizio Gardoni, Monica Di Luca

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Figure 4

Structural characterization of ADAM10/AP2 binding.

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Structural characterization of ADAM10/AP2 binding. (A) ADAM10 sequence i...
(A) ADAM10 sequence involved in binding the AP2 complex and its alignment with the most similar peptide sequence found in the PDB (Id: 1QWE) (B) Ribbon representation of the 1QWE peptide structure (PDB). Conserved aa are shown as red sticks with their backbone in orange. (C) Representation of the peptide–c-Src SH3 complex. The c-Src SH3 domain is represented in light gray ribbon and the interacting residues in gray stick. The interactions established by the 2 molecular partners are highlighted by dashed lines. (D) List of the interactions between the peptide and the c-Src SH3 domain. (E) Structural superposition between the residues of the c-Src SH3 domain and the β2 subunit of the AP2 complex colored in gray and black, respectively. The same color code in B was used for the peptide. (F) Ribbon representation of the structures of the c-Src SH3 domain and a portion of the β2 subunit of the AP2 complex, reported in light and dark gray, respectively. The interacting residues and the peptide are also shown.