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.
Highlights
Alzheimer’s disease (AD) is a progressive and irreversible brain disorder, which results in severe memory loss, behavioral as well as personality changes and a decline in cognitive abilities
These Ca2+ mobilizing effects of oligomeric Aβ42 were significantly greater than observed in cells exposed to Aβ42 that had been prepared in a manner to yield a monomeric form of the peptide (Figures S2, S1B)
We show that the oligomeric form of the AD-associated peptide Aβ42 has potent Ca2+ mobilizing properties and we identify mechanisms responsible for its action
Summary
Alzheimer’s disease (AD) is a progressive and irreversible brain disorder, which results in severe memory loss, behavioral as well as personality changes and a decline in cognitive abilities. The amyloid β-peptide (Aβ) is hypothesized to be central to the pathogenesis of both sporadic and familial AD (Hardy and Selkoe, 2002). An imbalance between the production and clearance of Aβ, as occurs in fAD and sAD, respectively, leads to the accumulation of Aβ and, in turn, to its aggregation. This aggregation process represents a critical step in the pathogenesis of AD because the neurotoxic properties of Aβ are associated only with aggregated forms of the peptide (Kuperstein et al, 2010). Protein aggregation is highly dynamic and involves a wide range of intermediate structures such as oligomers, comprising dimers, trimers, dodecamers, and higher-molecular weight complexes, before aggregating into protofibrils and into mature amyloid fibrils (Dobson, 2003)
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