Alzheimer's disease-associated peptide Aβ(42) mobilizes ER Ca(2+) via InsP(3)R-dependent and -independent mechanisms

Dysregulation of Ca(2+) homeostasis is considered to contribute to the toxic action of the Alzheimer's disease (AD)-associated amyloid-β-peptide (Aβ). Ca(2+) fluxes across the plasma membrane and release from intracellular stores have both been reported to underlie the Ca(2+) fluxes induced by Aβ(42). Here, we investigated the contribution of Ca(2+) release from the endoplasmic reticulum (ER) to the effects of Aβ(42) upon Ca(2+) homeostasis and the mechanism by which Aβ(42) elicited these effects. Consistent with previous reports, application of soluble oligomeric forms of Aβ(42) induced an elevation in intracellular Ca(2+). The Aβ(42)-stimulated Ca(2+) signals persisted in the absence of extracellular Ca(2+) indicating a significant contribution of Ca(2+) release from the ER Ca(2+) store to the generation of these signals. Moreover, inositol 1,4,5-trisphosphate (InsP(3)) signaling contributed to Aβ(42)-stimulated Ca(2+) release. The Ca(2+) mobilizing effect of Aβ(42) was also observed when applied to permeabilized cells deficient in InsP(3) receptors, revealing an additional direct effect of Aβ(42) upon the ER, and a mechanism for induction of toxicity by intracellular Aβ(42).