Alzheimer’s Disease-associated peptide Aβ42 mobilises ER Ca2+ via InsP3R-dependent and -independent mechanisms

• Main Authors: Laura E Allan, Geert eBultynck, Tomas eLuyten, Hozeefa eAmijee, Martin D Bootman, H Llewelyn eRoderick
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2013-11-01
• Series: Frontiers in Molecular Neuroscience
• Subjects: Endoplasmic Reticulum; signalling; Alzheimer’s disease; Aβ oligomers; calcium/Ca2+; InsP3/IP3
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fnmol.2013.00036/full

Dysregulation of Ca2+ homeostasis is considered to contribute to the toxic action of the Alzheimer’s Disease (AD) associated Amyloid-β-peptide (Aβ). Ca2+ fluxes across the plasma membrane and release from intracellular stores have both been reported to underlie the Ca2+ fluxes induced by Aβ42. Here, we investigated the contribution of Ca2+ release from the endoplasmic reticulum (ER) to the effects of Aβ42 upon Ca2+ 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 Ca2+. The Aβ42-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 (InsP3) signaling contributed to Aβ42-stimulated Ca2+ release. The Ca2+ 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.