Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca2+ via InsP3R-dependent and -independent mechanisms

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.

Vitamin D cell signalling in health and disease

“…The Ab protein can elevate intracellular Ca 2þ levels through different mechanisms [176,177]. It can bind to the cellular prion protein (PrP C ), which is coupled to mGluR5 to increase the formation of InsP 3 to release internal Ca 2þ [178].…”

In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca 2+ cross talk and loss of store-operated Ca 2+ entry (SOCE) in rat hippocampal neurons

“…Both Aβ and NMDA promote Ca 2+ influx but they also mobilize Ca 2+ from stores. Specifically, Aβ mobilizes ER Ca 2+ via IP 3 dependent and independent mechanisms [15]. Aβ and NMDA receptor activation cause mitochondrial dysfunction involving ER Ca 2+ release [16].…”

Dantrolene, A Treatment for Alzheimer Disease?

“…66-69 Up to date, the proposed mechanisms responsible for Ca 2+ dysregulation in AD primarily include overactivation of ryanodine receptors and InsP3R, which may contribute to early AD neuropathology and susceptibility. 35,70-74 …”