Regulation of NMDA receptor trafficking by amyloid-beta - PubMed (original) (raw)

doi: 10.1038/nn1503. Epub 2005 Jul 17.

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• PMID: 16025111
• DOI: 10.1038/nn1503

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Regulation of NMDA receptor trafficking by amyloid-beta

Eric M Snyder et al. Nat Neurosci. 2005 Aug.

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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.

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Comment in

• The synaptic Abeta hypothesis of Alzheimer disease.
  Tanzi RE. Tanzi RE. Nat Neurosci. 2005 Aug;8(8):977-9. doi: 10.1038/nn0805-977. Nat Neurosci. 2005. PMID: 16047022 No abstract available.

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