Regulation of NMDA receptor trafficking by amyloid-

Eric M Snyder^1, 6, Yi Nong², Claudia G Almeida³, Surojit Paul⁴, Timothy Moran², Eun Young Choi¹, Angus C Nairn^1, 5, Michael W Salter², Paul J Lombroso⁴, Gunnar K Gouras³ & Paul Greengard¹

¹  Laboratory for Molecular and Cellular Neuroscience, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.

²  Program in Brain and Behavior, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.

³  Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, New York, 10021, USA.

⁴  The Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, Connecticut 06520, USA.

⁵  Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, Connecticut 06508, USA.

⁶  Current address: McKinsey and Company, 600 Campus Drive, Florham Park, New Jersey 07932, USA.

Amyloid- peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid- reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid- 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- by treating neurons with a -secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid- application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-−dependent endocytosis of NMDA receptors required the -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- can cause synaptic dysfunction and contribute to Alzheimer disease pathology.

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