Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vivo
Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vivo
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DOI：
10.1093/jnen/63.3.255
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发表时间：
2004-03-01
影响因子：
3.2
通讯作者：
Mori, H
中科院分区：
文献类型：
--
作者：
Takuma, H;Tomiyama, T;Mori, H
淀粉样蛋白肽（Abeta）被广泛认为在阿尔茨海默病（AD）中起着核心的病因学作用。AP已被证明对神经细胞有细胞毒性作用，尽管其作用机制尚不清楚。为了研究凋亡级联在β诱导的细胞死亡中的作用，我们使用了caspase-3 （cpp32）缺失的小鼠，这是该级联的关键蛋白酶。我们将β(1-40)微量注射到成年小鼠大脑的海马区，因为阿尔茨海默病是一种成人发病的疾病。我们发现野生型小鼠海马区有明显的细胞损失，caspase-3缺陷小鼠的神经元细胞死亡得到了显著的拯救，这与基因剂量效应有关。除成年小鼠外，我们观察到从caspase-3缺陷小鼠的胎脑中制备的培养神经元几乎没有abeta诱导的死亡，但在野生型小鼠中确实观察到这种神经元的死亡。野生型小鼠和caspase3 -3缺失小鼠在abeta诱导的神经元死亡中差异非常显著，表明在体内和体外，abeta诱导的神经元死亡均通过caspase3凋亡级联介导。
Amyloid beta peptide (Abeta) is widely believed to play a central and etiological role in Alzheimer disease (AD). AP has been shown to have cytotoxic effects in neural cells, although the mechanism by which it does this is still unclear. To examine the involvement of the apoptotic cascade in Abeta-induced cell death, we used mice deficient in caspase-3 (CPP 32), a key protease in this cascade. We microinjected Abeta(1-40) into hippocampal regions of the brains of adult mice because AD is an adult-onset disease. We found significant cellular loss in the hippocampal regions of wild-type mice and dramatic rescue of neuronal cell death in caspase-3-deficient mice, with a gene dosage effect. In addition to adult mice, we observed little Abeta-induced death of cultured neurons prepared from fetal brains of caspase-3-deficient mice but did observe death of such neurons from wild-type mice. The difference in Abeta-induced neuronal death between wild-type and caspase-3-deficient mice was highly significant, indicating that Abeta-induced neuronal death is mediated in vivo as well as in vitro by the caspase3 apoptotic cascade.