Abstract
Amyloid-β peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-β reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-β 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-β by treating neurons with a γ-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-β application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-βâdependent endocytosis of NMDA receptors required the α-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-β can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
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Acknowledgements
We thank M. Greenberg for the gift of phospho-NR2B antibody and G. Thinakaran and S. Sisodia for the gift of stably transfected N2A cells. We also thank J. Shepherd and members of the Greengard and Gouras labs for helpful discussions. This work was supported by the Fisher Foundation for Alzheimer's Research, US National Institutes of Health grant AG09464 (P.G.T. and G.K.G.) and National Institute of Mental Health grant 52711 and 01527 (P.J.L.).
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Supplementary information
Supplementary Fig. 1
Methyllycaconitine (MLA) inhibits the effect of amyloid-β on NMDA receptors. (PDF 478 kb)
Supplementary Fig. 2
Model of amyloid-β regulation of glutamate receptor trafficking. (PDF 1752 kb)
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Snyder, E., Nong, Y., Almeida, C. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nat Neurosci 8, 1051â1058 (2005). https://doi.org/10.1038/nn1503
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DOI: https://doi.org/10.1038/nn1503
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