Apoptosis induced by Aβ25–35 peptide is Ca²⁺‐IP₃ signaling‐dependent in murine astrocytes

Abstract

Although the accumulation of the neurotoxic peptide β-amyloid (Aβ) in the central nervous system is a hallmark of Alzheimer's disease, whether Aβ acts in astrocytes is unclear, and downstream functional consequences have yet to be defined. Here, we show that cytosolic Ca(2+) dysregulation, induced by a neurotoxic fragment (Aβ25-35), caused apoptosis in a concentration-dependent manner, leading to cytoplasmic Ca(2+) mobilization from extra- and intracellular sources, mainly from the endoplasmic reticulum (ER) via IP3 receptor activation. This mechanism was related to Aβ-mediated apoptosis by the intrinsic pathway because the expression of pro-apoptotic Bax was accompanied by its translocation in cells transfected with GFP-Bax. Aβ-mediated apoptosis was reduced by BAPTA-AM, a fast Ca(2+) chelator, indicating that an increase in intracellular Ca(2+) was involved in cell death. Interestingly, the Bax translocation was dependent on Ca(2+) mobilization from IP3 receptors because pre-incubation with xestospongin C, a selective IP3 receptor inhibitor, abolished this response. Taken together, these results provide evidence that Aβ dysregulation of Ca(2+) homeostasis induces ER depletion of Ca(2+) stores and leads to apoptosis; this mechanism plays a significant role in Aβ apoptotic cell death and might be a new target for neurodegeneration treatments.

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…It was shown that treatment with the calcium chelator (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) reduced Ab-mediated apoptosis in astrocytes. Thus, it has been concluded that the Ab fragment modulates IP 3 R activity, increases IICR and leads to the apoptosis observed in AD [119].…”

HSF1 Relieves Amyloid-β-Induced Cardiomyocytes Apoptosis

“…Bax and Bcl-2 are two important proteins related to apoptosis, their ratio is associated with the opening of the mitochondrion permeability transition pore (MPTP) and release of cytochrome C. Regulation of Bax and Bcl-2 by amyloid-b suggested that apoptosis induced by amyloid-b may be associated with mitochondrial-mediated apoptosis. Apoptosis induced by amyloid-b also appears in brains [6,24] which is another place for amyloid-b accumulation. Changes in cytoskeleton as well as phosphorylation of RhoA and ROCK were also found after treatment with amyloid-b.…”

“…Meanwhile, amyloid-b has impacts on intracellular concentration of Ca 2? , changes the membrane permeability of mitochondria resulting in release of cytochrome C and ROS, leading to apoptosis [5,6].…”

Intrahippocampal Pathways Involved in Learning/Memory Mechanisms are Affected by Intracerebral Infusions of Amyloid-β25-35 Peptide and Hydrated Fullerene C60 in Rats

“…In our previous study, we have revealed С60HyFn-produced inhibition of intracellular Аβ1-42 deposit formation associated with exogenous fibrillar Аβ25-35 [29] and, supposedly, with its endogenous fullerene-disaggregated form [11]. С60HyFn ability to block both intracellular Аβ1-42 generation and the extracellular glutamate receptors activity [63] reducing Ca 2+ inflow, one of the main sources of Аβ25-35 neurotoxicity [64]). These mechanisms are expected to "intercept" the development of the Аβ25-35-associated effects and, in that way, protecting the network connections between different hippocampal areas, survival rate of their neurons, and, finally, memory functioning.…”