Amyloid-? proteins activate Ca2+-permeable channels through calcium-sensing receptors

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Abstract
The amyloid‐beta peptides (Aβ) are produced in excess in Alzheimer's disease (AD) and may contribute to neuronal dysfunction and degeneration. This study provides strong evidence for a novel cellular target for the actions of Aβ, the phospholipase C‐coupled, extracellular Ca2+‐sensing receptor (CaR). We demonstrate that Aβs produce a CaR‐mediated activation of a Ca2+‐permeable, nonselective cation channel (NCC), probably via elevation in cytosolic Ca2+ (Cai), in cultured hippocampal pyramidal neurons from normal rats and from wild type mice but not those from mice with targeted disruption of the CaR gene (CaR −/−). Aβs also activate NCC in CaR‐transfected but not in nontransfected human embryonic kidney (HEK293) cells. Thus aggregates of Aβ deposited on hippocampal neurons in AD could inappropriately activate the CaR, stimulating Ca2+‐permeable channels and causing sustained elevation of Cai with resultant neuronal dysfunction. © 1997 Wiley‐Liss Inc.