title: Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca(2+) via InsP3R-dependent and -independent mechanisms.
abstract: 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 Aβ42. Here, we investigated the contribution of Ca(2+) release from the endoplasmic reticulum (ER) to the effects of Aβ42 upon Ca(2+) homeostasis and the mechanism by which Aβ42 elicited these effects. Consistent with previous reports, application of soluble oligomeric forms of Aβ42 induced an elevation in intracellular Ca(2+). The Aβ42-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 (InsP3) signaling contributed to Aβ42-stimulated Ca(2+) release. The Ca(2+) mobilizing effect of Aβ42 was also observed when applied to permeabilized cells deficient in InsP3 receptors, revealing an additional direct effect of Aβ42 upon the ER, and a mechanism for induction of toxicity by intracellular Aβ42.
authors.affiliation: Babraham Institute, Babraham Research Campus Babraham, Cambridge, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Jensen
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Tomas
authors.initials: T
authors.lastname: Luyten
authors.forename: Hozeefa
authors.initials: H
authors.lastname: Amijee
authors.forename: Martin D
authors.initials: MD
authors.lastname: Bootman
authors.forename: H Llewelyn
authors.initials: HL
authors.lastname: Roderick
keywords: Alzheimer's disease; Aβ oligomers; InsP3 receptors/InsP3Rs; InsP3/IP3; calcium/Ca2+; endoplasmic reticulum/ER