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Apoptosis induced by Aβ25–35 peptide is Ca 2+ ‐ IP 3 signaling‐dependent in murine astrocytes
Author(s) -
Oseki K. T.,
Monteforte P. T.,
Pereira G. J. S.,
Hirata H.,
Ureshino R. P.,
Bincoletto C.,
Hsu Y.T.,
Smaili S. S.
Publication year - 2014
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12599
Subject(s) - microbiology and biotechnology , apoptosis , neurodegeneration , endoplasmic reticulum , programmed cell death , cytosol , bapta , intracellular , receptor , signal transduction , transfection , biology , chemistry , cell culture , biochemistry , medicine , genetics , disease , enzyme
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 IP 3 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 IP 3 receptors because pre‐incubation with xestospongin C, a selective IP 3 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.