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Regulation of NMDA receptor trafficking by amyloid-β

Nature Neuroscience volume 8, pages 1051–1058 (2005)Cite this article

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-β–dependent 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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Figure 1: Amyloid-β1–42 promotes endocytosis of glutamate receptor subunits.
Figure 2: Amyloid-β (Aβ) reduces synaptic NMDA receptors.
Figure 3: Naturally secreted amyloid-β reduces surface NMDA receptors.
Figure 4: Amyloid-β reduces surface expression of NMDA receptors through α-7 nicotinic receptors and PP2B.
Figure 5: Amyloid-β promotes dephosphorylation of STEP, which controls glutamate receptor trafficking.
Figure 6: Amyloid-β depresses NMDA receptor (NMDAR) currents.
Figure 7: Amyloid-β reduces NMDA-induced CREB phosphorylation.

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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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Author notes

  1. Eric M Snyder

    Present address: McKinsey and Company, 600 Campus Drive, Florham Park, New Jersey, 07932, USA

Authors and Affiliations

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

    Eric M Snyder, Eun Young Choi, Angus C Nairn & Paul Greengard

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

    Yi Nong, Timothy Moran & Michael W Salter

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

    Claudia G Almeida & Gunnar K Gouras

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

    Surojit Paul & Paul J Lombroso

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

    Angus C Nairn

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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)

Supplementary Methods (PDF 65 kb)

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Snyder, E., Nong, Y., Almeida, C. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nat Neurosci 8, 1051–1058 (2005). https://doi.org/10.1038/nn1503

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