PMID:16025111

Citation	Snyder, EM, Nong, Y, Almeida, CG, Paul, S, Moran, T, Choi, EY, Nairn, AC, Salter, MW, Lombroso, PJ, Gouras, GK and Greengard, P (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci. 8:1051-8
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.
Links	PubMed Online version:10.1038/nn1503
Keywords	Alzheimer Disease/genetics; Alzheimer Disease/metabolism; Amyloid beta-Peptides/pharmacology; Amyloid beta-Peptides/physiology; Amyloid beta-Protein Precursor/genetics; Animals; CREB-Binding Protein; Calcineurin/physiology; Cell Membrane/metabolism; Cerebral Cortex/metabolism; Disease Models, Animal; Electric Conductivity; Endocytosis/drug effects; Enzyme Activation/drug effects; Mice; N-Methylaspartate/pharmacology; Neurons/drug effects; Neurons/metabolism; Neurons/physiology; Nuclear Proteins/metabolism; Peptide Fragments/pharmacology; Protein Transport/physiology; Protein Tyrosine Phosphatases/metabolism; Protein Tyrosine Phosphatases, Non-Receptor; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate/metabolism; Receptors, Nicotinic/physiology; Signal Transduction/drug effects; Synapses/metabolism; Trans-Activators/metabolism
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