Regulation of NMDA receptor trafficking by amyloid-β

✍ Scribed by Snyder, Eric M; Nong, Yi; Almeida, Claudia G; Paul, Surojit; Moran, Timothy; Choi, Eun Young; Nairn, Angus C; Salter, Michael W; Lombroso, Paul J; Gouras, Gunnar K

• Book ID: 109940654
• Publisher: Nature Publishing Group
• Year: 2005
• Tongue: English
• Weight: 365 KB
• Volume: 8
• Category: Article
• ISSN: 1097-6256
• DOI: 10.1038/nn1503

✦ Synopsis

Amyloid-b peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-b reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-b promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-b by treating neurons with a c-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-b application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-bdependent endocytosis of NMDA receptors required the a-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-b can cause synaptic dysfunction and contribute to Alzheimer disease pathology.