P38 activation mediates amyloid-beta cytotoxicity.
P38 activation mediates amyloid-beta cytotoxicity.
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P38 激活介导β淀粉样蛋白细胞毒性。
DOI：
10.1007/s11064-005-6872-x
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发表时间：
2005
影响因子：
4.4
通讯作者：
Smith,MarkA
中科院分区：
文献类型：
--
作者：
Zhu,Xiongwei;Mei,Matthew;Lee,Hyoung-Gon;Wang,Yang;Han,Jiahuai;Perry,George;Smith,MarkA
淀粉样蛋白-β是阿尔茨海默病(AD)发病的主要候选因素，但其机制尚不清楚。因此，有相当大的兴趣的证据表明，淀粉样蛋白-β引起的神经元损伤是由氧化应激介导的。值得注意的是，氧化应激导致应激激活蛋白激酶的激活，我们和其他人已经证明，这也参与了AD的发病。一个SAPK，p38，似乎在AD中是至关重要的，因此，在目前的研究中，我们研究了p38激活在淀粉样蛋白β细胞毒性中的作用。我们的数据显示，淀粉样蛋白-β以浓度依赖的方式诱导M17人神经母细胞瘤细胞的p38激活。值得注意的是，通过过度表达显性负p38来抑制p38活性，显著降低了淀粉样蛋白-β的毒性。与此一致的是，在原代皮质神经元中，淀粉样蛋白β也诱导了p38的激活，当p38被其特异性抑制剂SB203580抑制时，淀粉样蛋白β的毒性显著降低。综上所述，这些数据表明，p38是淀粉样蛋白β诱导的神经元死亡的关键下游效应因子，阻断这一途径可能具有治疗价值。
Amyloid-β is a leading candidate factor in the development of Alzheimer disease (AD), however the mechanisms involved are unclear. As such, there has been considerable interest in evidence showing that the neuronal damage caused by amyloid-β is mediated by oxidative stress. Notably, oxidative stress leads to activation of stress-activated protein kinases, which we and others have shown are also involved in AD pathogenesis. One SAPK in particular, p38, appears to be crucial in AD and therefore, in the current study, we investigated the role of p38 activation in amyloid-β cytotoxicity. Our data showed p38 activation was induced by amyloid-β in a concentration-dependent manner in M17 human neuroblastoma cells. Notably, amyloid-β toxicity was significantly decreased by inhibition of p38 activity by overexpressing dominant negative p38. Consistent with this, in primary cortical neurons amyloid-β also induced p38 activation and amyloid-β toxicity was significantly diminished when p38 was inhibited by its specific inhibitor, SB203580. Taken together, these data suggest that p38 is a key downstream effector of amyloid-β-induced neuronal death and blocking this pathway may be of therapeutic value.