| Literature DB >> 16025111 |
Eric M Snyder1, Yi Nong, Claudia G Almeida, Surojit Paul, Timothy Moran, Eun Young Choi, Angus C Nairn, Michael W Salter, Paul J Lombroso, Gunnar K Gouras, Paul Greengard.
Abstract
Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta 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-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-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-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.Entities:
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Year: 2005 PMID： 16025111 DOI： 10.1038/nn1503
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884