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首页> 外文期刊>The European Journal of Neuroscience >Apoptosis induced by Aβ25-35 peptide is Ca2+-IP3 signaling-dependent in murine astrocytes
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Apoptosis induced by Aβ25-35 peptide is Ca2+-IP3 signaling-dependent in murine astrocytes

机译:Aβ25-35肽诱导的凋亡在鼠星形胶质细胞中是Ca2 + -IP3信号依赖的。

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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 Ca2+ dysregulation, induced by a neurotoxic fragment (Aβ25-35), 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 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 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 Aβ dysregulation of Ca2+ homeostasis induces ER depletion of Ca2+ 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.
机译:尽管神经毒性肽β-淀粉样蛋白(Aβ)在中枢神经系统中的积累是阿尔茨海默氏病的标志,但尚不清楚Aβ是否在星形胶质细胞中起作用,下游功能的后果尚待确定。在这里,我们显示由神经毒性片段(Aβ25-35)诱导的胞质Ca2 +失调以浓度依赖性方式引起凋亡,导致细胞质Ca2 +从细胞外和细胞内来源动员,主要是通过内质网(ER)通过IP3受体激活。该机制与内在途径通过Aβ介导的细胞凋亡有关,因为促凋亡Bax的表达伴随着其在转染GFP-Bax的细胞中的易位。 BAPTA-AM(一种快速的Ca2 +螯合剂)减少了Aβ介导的细胞凋亡,表明细胞内Ca2 +的增加与细胞死亡有关。有趣的是,Bax移位依赖于IP3受体的Ca2 +动员,因为与xestospongin C(一种选择性IP3受体抑制剂)的预孵育消除了这种应答。综上所述,这些结果提供了证据,证明Aβ对Ca2 +稳态的失调可诱导Ca2 +储备的ER消耗并导致细胞凋亡。这种机制在Aβ细胞凋亡中起重要作用,并且可能成为神经退行性疾病治疗的新靶标。

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