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

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.