Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca2+ via InsP3R-dependent and -independent mechanisms

Dysregulation of Ca2+ homeostasis is considered to contribute to the toxic action of the Alzheimer's disease (AD)-associated amyloid-beta-peptide (4). Ca2+ fluxes across the plasma membrane and release from intracellular stores have both been reported to underlie the Ca2+ fluxes induced by A beta(42). Here, we investigated the contribution of Ca2+ release from the endoplasmic reticulum (ER) to the effects of A beta(42) upon Ca2+ homeostasis and the mechanism by which A beta(42) elicited these effects. Consistent with previous reports, application of soluble oligomeric forms of A beta(42) induced an elevation in intracellular Ca2+. The A beta(42)-stimulated Ca2+ signals persisted in the absence of extracellular Ca2+ indicating a significant contribution of Ca2+ release from the ER Ca2+ store to the generation of these signals. Moreover, inositol 1,4,5-trisphosphate (InsP(3)) signaling contributed to A beta(42)-stimulated Ca2+ release. The Ca2+ mobilizing effect of A beta(42) was also observed when applied to permeabilized cells deficient in InsP(3) receptors, revealing an additional direct effect of A beta(42) upon the ER, and a mechanism for induction of toxicity by intracellular A beta(42).