AUTHOR=Allan Laura E., Bultynck Geert , Luyten Tomas , Amijee Hozeefa , Bootman Martin D., Roderick H Llewelyn TITLE=Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca2+ via InsP3R-dependent and -independent mechanisms JOURNAL=Frontiers in Molecular Neuroscience VOLUME=6 YEAR=2013 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2013.00036 DOI=10.3389/fnmol.2013.00036 ISSN=1662-5099 ABSTRACT=

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.