Apoptosis induced by Aβ25-35 peptide is Ca(2+) -IP3 signaling-dependent in murine astrocytes.
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.
Department of Pharmacology, EPM, Federal University of São Paulo (UNIFESP), Rua Três de Maio 100, CEP: 04044-020, São Paulo, SP, Brazil.
K T
KT
Oseki
P T
PT
Monteforte
G J S
GJ
Pereira
H
H
Hirata
R P
RP
Ureshino
C
C
Bincoletto
Y-T
YT
Hsu
S S
SS
Smaili
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35)
Alzheimer's disease; Bax; amyloid-beta peptide; apoptosis; calcium signaling; endoplasmic reticulum