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


Liu, SJ and Gasperini, R and Foa, L and Small, DH, Amyloid-beta Decreases Cell-Surface AMPA Receptors by Increasing Intracellular Calcium and Phosphorylation of GluR2, Journal of Alzheimer's Disease, 21, (2) pp. 655-666. ISSN 1387-2877 (2010) [Refereed Article]

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Copyright Statement

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

DOI: doi:10.3233/JAD-2010-091654


-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 A 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. A 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 A and Bay K 8644. Taken together, these results demonstrate that A 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 A 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.

Item Details

Item Type:Refereed Article
Keywords:Alzheimer's disease, AMPA, amyloid-beta, calcium, GluR2, phospho-GluR2, PKC
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Liu, SJ (Dr Shijie Liu)
UTAS Author:Gasperini, R (Dr Rob Gasperini)
UTAS Author:Foa, L (Professor Lisa Foa)
UTAS Author:Small, DH (Professor David Small)
ID Code:64944
Year Published:2010
Web of Science® Times Cited:49
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-09-16
Last Modified:2012-03-01

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