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

Although many of the biochemical mechanisms which regulate production or clearance of the amyloid-beta protein (Abeta) of Alzheimer's disease (AD) are now well understood, the mechanism of Abeta neurotoxicity remains unclear. A number of studies have shown that Abeta can disrupt neuronal Ca(2+) homeostasis by inducing influx of extracellular Ca(2+) into the neuronal cytoplasm. Ca(2+) is known to play an important role in neuronal excitability, synaptic plasticity and neurotoxicity. Therefore, Abeta-induced Ca(2+) dysregulation may contribute to many of the cognitive and neuropathologic features of AD. In vitro studies show that Abeta can increase ion permeability in lipid membranes. This increased permeability is reportedly associated with the formation of artificial ion pores formed from Abeta oligomers. However, a number of other studies show that Abeta can activate endogenous ion channels on the cell surface. There is also increasing evidence that presenilin mutations alter intracellular Ca(2+) stores. It is likely that elucidation of the mechanism by which Abeta and presenilin cause Ca(2+) dysregulation in neurons will help to identify new drug targets for the treatment of AD.