Department of Pathophysiology, Key Laboratory of Neurological Diseases of Educational Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Alzheimers Dis. 2010;20(1):145-57. doi: 10.3233/JAD-2010-1351.
It has been a puzzle why the tangle-bearing neurons in Alzheimer's disease (AD) brain do not die preferentially of apoptosis even though they are actually challenged by multiple proapoptotic factors. Recently, we have reported that phosphorylation of tau can antagonize apoptosis induced by exogenous apoptotic inducers. Amyloid-beta (Abeta), a recognized endogenous proapoptotic factor, is significantly increased in the AD brains, however, it is not known whether tau could abate the Abeta-potentiated apoptosis. Here, we observed that the cells bearing high level of Abeta were more vulnerable than the controls to H2O2-induced apoptosis, and this effect of Abeta was associated with decrease of Bcl-2, elevation of Bax and cytosolic cytochrome-c, as well as activation of caspase-3, suggesting that Abeta could potentiate the oxidant-induced cell apoptosis with involvement of mitochondria-caspase-3 pathway. More importantly, we also found that expression of tau that became hyperphosphorylated could reduce the Abeta-potentiated apoptosis with simultaneous preservation of Bcl-2 and suppression of Bax, cytosolic cytochrome-c, and caspase-3 activity, implying that overexpression of tau that became hyperphosphorylated can attenuate the Abeta-potentiated cell apoptosis through mitochondria-caspase-3 pathway. These findings provide an explanation of the chronic nature of neurodegeneration of neurons with neurofibrillary pathology of abnormal hyperphosphorylated tau in AD and related tauopathies.
阿尔茨海默病（AD）脑中携带缠结的神经元尽管实际上受到多种促凋亡因素的挑战，但为什么不会优先通过细胞凋亡死亡一直是一个谜。最近，我们报道了 tau 的磷酸化可以拮抗外源性凋亡诱导剂诱导的凋亡。淀粉样蛋白-β（Abeta）是一种公认的内源性促凋亡因子，在 AD 脑中显著增加，然而，tau 是否可以减轻 Abeta 增强的凋亡尚不清楚。在这里，我们观察到携带高水平 Abeta 的细胞比对照细胞更容易受到 H2O2 诱导的凋亡，并且这种 Abeta 的作用与 Bcl-2 的减少、Bax 的增加和细胞质细胞色素-c 以及 caspase-3 的激活有关，表明 Abeta 可以通过线粒体-caspase-3 途径增强氧化剂诱导的细胞凋亡。更重要的是，我们还发现，过度磷酸化的 tau 的表达可以降低 Abeta 增强的凋亡，同时保留 Bcl-2 并抑制 Bax、细胞质细胞色素-c 和 caspase-3 活性，这表明过度表达过度磷酸化的 tau 可以通过线粒体-caspase-3 途径减轻 Abeta 增强的细胞凋亡。这些发现为 AD 和相关 tau 病中具有异常过度磷酸化 tau 的神经纤维缠结的神经元神经退行性变的慢性性质提供了一种解释。
