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Amyloid-beta Decreases Cell-Surface AMPA Receptors by Increasing Intracellular Calcium and Phosphorylation of GluR2

journal contribution
posted on 2023-05-17, 03:12 authored by Liu, SJ, Robert GasperiniRobert Gasperini, Lisa FoaLisa Foa, David SmallDavid Small
á-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are key regulators of synaptic function and cognition. In Alzheimer's disease (AD), cell-surface AMPARs are downregulated, however the reason for this downregulation is not clear. In the present study, we found that Aâ significantly decreased levels of the cell-surface AMPA-type glutamate receptor subunit 2 (GluR2), and increased the concentration of free cytosolic calcium ion ([Ca2+]i) in hippocampal neurons. Ion channel blockers (nifedipine, tetrodotoxin, SKF96365) decreased [Ca2+ and increased the level of cell-surface GluR2, whereas Bay K 8644, an activator of L-type voltage-gated calcium channels increased [Ca2+]i and decreased cell-surface GluR2. Aâ and Bay K 8644 increased phosphorylation of serine-880 (S880) on GluR2, whereas the nifedipine. tetrodotoxin and SKF96365 decreased S880 phosphorylation. Finally, we found that bisindolylmeimide I (GF 109203X, GFX), an inhibitor of protein kinase C (PKC) blocked both the decrease in cell-surface GluR2 and the increase in phospho-S880 induced by Aâ and Bay K 8644. Taken together, these results demonstrate that Aâ decreases cell-surface GluR2 by increasing PKC-mediated phosphorylation of S880. Our study supports the view that a rise in cytosolic [Ca2+]i induced by Aâ could impair synaptic function by decreasing the availability of AMPARs at the synapse. This decrease in AMPARs may contribute to the decline in cognitive function seen in AD.

History

Publication title

Journal of Alzheimer's Disease

Volume

21

Pagination

655-666

ISSN

1387-2877

Department/School

Menzies Institute for Medical Research

Publisher

I O S Press

Place of publication

Netherlands

Rights statement

© 2010 - lOS Press and the authors. All rights reserved.

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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