Qian Min-cai, Liu Jing, Yao Jia-shu, Wang Wei-min, Yang Jian-hong, Wei Li-li, Shen Yue-di, Chen Wei
Department of Psychiatry, Third People's Hospital of Huzhou, Huzhou, 313000, Zhejiang, China.
J Mol Neurosci. 2015 Jun;56(2):491-9. doi: 10.1007/s12031-015-0498-5. Epub 2015 Feb 3.
The pathogenesis of Alzheimer's disease (AD) is very complex and there are currently no significant treatments for the disease. Caspase-8 is known to be involved in neuronal apoptosis. To explore a possible molecular mechanisms involved in AD pathology, this study investigated the effect of caspase-8 knockdown on amyloid-β 1-40 (Aβ1-40)-induced apoptosis in PC12 cells. The proliferation of PC12 cells was significantly inhibited in Aβ-treated cells, and a high fraction of the cells underwent apoptosis in a dose- and time-dependent manner. Transfection of caspase-8 small interfering RNA (siRNA) resulted in reduced apoptosis following Aβ1-40 treatment. The activation of caspase-3, caspase-8, and caspase-9 was stimulated by Aβ1-40, an effect that was also significantly reduced by caspase-8 siRNA. Knockdown of caspase-8 increased the phosphorylation of the signaling molecules AKT and ERK1/2 relative to cells treated with Aβ1-40 alone. Caspase-8 is an important effector molecule involved in apoptosis induced by Aβ1-40 and is likely involved in AD pathology. This study suggests that targeted inhibition of caspase-8 may be a new therapeutic for preventing neuronal apoptosis and inhibiting the progression of AD.
阿尔茨海默病（AD）的发病机制非常复杂，目前尚无有效的治疗方法。已知半胱天冬酶-8参与神经元凋亡。为了探究AD病理过程中可能涉及的分子机制，本研究调查了半胱天冬酶-8基因敲低对淀粉样β蛋白1-40（Aβ1-40）诱导的PC12细胞凋亡的影响。在Aβ处理的细胞中，PC12细胞的增殖受到显著抑制，并且大量细胞以剂量和时间依赖性方式发生凋亡。转染半胱天冬酶-8小干扰RNA（siRNA）可减少Aβ1-40处理后的细胞凋亡。Aβ1-40刺激了半胱天冬酶-3、半胱天冬酶-8和半胱天冬酶-9的激活，而半胱天冬酶-8 siRNA也显著降低了这种作用。与仅用Aβ1-40处理的细胞相比，敲低半胱天冬酶-8可增加信号分子AKT和ERK1/2的磷酸化。半胱天冬酶-8是Aβ1-40诱导凋亡过程中的重要效应分子，可能参与AD的病理过程。本研究表明，靶向抑制半胱天冬酶-8可能是预防神经元凋亡和抑制AD进展的一种新的治疗方法。
