ADAM10 in Synaptic Physiology and Pathology

作者：Musardo Stefano; Marcello Elena; Gardoni Fabrizio; Di Luca Monica^*

来源：Neurodegenerative Diseases, 2014, 13(2-3): 72-74.

DOI：10.1159/000354233

• ADAM10
• Clathrin adaptor protein 2 complex
• Trafficking
• Alzheimer's disease
• Long-term depression
• Long-term potentiation
• Synapse-associated protein 97

Background: Generation of amyloid-beta peptide is at the beginning of a cascade that leads to Alzheimer's disease. Amyloid precursor protein (APP) as well as beta- and gamma-secretases are the principal players involved in amyloid-beta (A beta) production, while alpha-secretase cleavage on APP prevents A beta deposition. A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to act as alpha-secretase in neurons. Objective: Although localization of ADAM10 in the synaptic membrane is the key for its shedding activity, currently, very little is known about the mechanisms that control the synaptic abundance of ADAM10. Results: Two established forms of long-term activity-dependent plasticity, i.e. long-term potentiation and long-term depression (LTD), differentially regulate the synaptic availability and activity of ADAM10. Longterm potentiation decreases ADAM10 surface levels and activity by promoting its endocytosis. This process is mediated by activity-regulated association of ADAM10 with the clathrin adaptor protein 2 (AP2) complex. Conversely, LTD fosters ADAM10 insertion in the membrane and stimulates its activity. Furthermore, ADAM10 interaction with synapse-associated protein 97 (SAP97) is necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced spine morphology changes. Conclusions: Regulated interaction of ADAM10 with SAP97 and AP2 discloses a novel physiological mechanism of ADAM10 activity regulation at the synapses. This phenomenon produces a situation whereby synaptically regulated ADAM10 activity is positioned to modulate synaptic functioning.

• 出版日期2014