Apoptosis induced by A beta 25-35 peptide is Ca2+-IP3 signaling-dependent in murine astrocytes

Apoptosis induced by A beta 25-35 peptide is Ca2+-IP3 signaling-dependent in murine astrocytes

Author Oseki, K. T. Autor UNIFESP Google Scholar
Monteforte, P. T. Autor UNIFESP Google Scholar
Pereira, G. J. S. Autor UNIFESP Google Scholar
Hirata, H. Autor UNIFESP Google Scholar
Ureshino, R. P. Autor UNIFESP Google Scholar
Bincoletto, C. Autor UNIFESP Google Scholar
Hsu, Y. -T. Google Scholar
Smaili, Soraya Soubhi Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Med Univ S Carolina
Abstract Although the accumulation of the neurotoxic peptide beta-amyloid (A beta) in the central nervous system is a hallmark of Alzheimer's disease, whether A beta acts in astrocytes is unclear, and downstream functional consequences have yet to be defined. Here, we show that cytosolic Ca2+ dysregulation, induced by a neurotoxic fragment (A beta 25-35), caused apoptosis in a concentration-dependent manner, leading to cytoplasmic Ca2+ mobilization from extra-and intracellular sources, mainly from the endoplasmic reticulum (ER) via IP3 receptor activation. This mechanism was related to A beta-mediated apoptosis by the intrinsic pathway because the expression of pro-apoptotic Bax was accompanied by its translocation in cells transfected with GFP-Bax. A beta-mediated apoptosis was reduced by BAPTA-AM, a fast Ca2+ chelator, indicating that an increase in intracellular Ca2+ was involved in cell death. Interestingly, the Bax translocation was dependent on Ca2+ 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 A beta dysregulation of Ca2+ homeostasis induces ER depletion of Ca2+ stores and leads to apoptosis; this mechanism plays a significant role in A beta apoptotic cell death and might be a new target for neurodegeneration treatments.
Keywords Alzheimer's disease
amyloid-beta peptide
calcium signaling
endoplasmic reticulum
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number NIH: NS40932
Date 2014-08-01
Published in European Journal of Neuroscience. Hoboken: Wiley-Blackwell, v. 40, n. 3, p. 2471-2478, 2014.
ISSN 0953-816X (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 2471-2478
Origin http://dx.doi.org/10.1111/ejn.12599
Access rights Closed access
Type Article
Web of Science ID WOS:000340502500001
URI http://repositorio.unifesp.br/handle/11600/38064

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