Cente Martin, Mandakova Stanislava, Filipcik Peter
Institute of Neuroimmunology, Slovak Academy of Sciences, 845 10 Bratislava, Slovakia.
Cell Mol Neurobiol. 2009 Sep;29(6-7):945-9. doi: 10.1007/s10571-009-9379-1. Epub 2009 Mar 17.
We have previously shown that human misfolded tau proteins strongly perturb mitochondrial transport and induce accumulation of free radicals in neurons. This interference is underlying cause of increased susceptibility to oxidative stress and could be linked to excitotoxic pathways. In order to understand integral mechanisms of misfolded tau driven neurodegeneration, we have investigated the role of human truncated tau protein, derived from Alzheimer's disease, in rat cortical neurons under the conditions of excitotoxic stress induced by glutamate. We found that primary neurons expressing truncated tau protein are highly susceptible to glutamate-induced cell death. Pre-treatment with memantine (N-methyl-D-aspartate receptor antagonist) significantly improved survival of rat neurons exposed to glutamate and its effect was associated with overall decrease of reactive oxygen species (ROS) in both transgenic and nontransgenic neurons. Interestingly, despite of this overall effect, memantine was not able to decrease misfolded tau-induced ROS level specifically in transgenic cells. Our data suggest that memantine does not interfere with specific pathological pathways induced by misfolded tau protein nevertheless is able to attenuate oxidative stress in neurons.
我们之前已经表明，人类错误折叠的tau蛋白会强烈干扰线粒体运输，并诱导神经元中自由基的积累。这种干扰是对氧化应激易感性增加的根本原因，并且可能与兴奋性毒性途径有关。为了了解错误折叠的tau蛋白驱动神经退行性变的整体机制，我们研究了源自阿尔茨海默病的人类截短型tau蛋白在谷氨酸诱导的兴奋性毒性应激条件下对大鼠皮质神经元的作用。我们发现，表达截短型tau蛋白的原代神经元对谷氨酸诱导的细胞死亡高度敏感。用美金刚（N-甲基-D-天冬氨酸受体拮抗剂）预处理可显著提高暴露于谷氨酸的大鼠神经元的存活率，其作用与转基因和非转基因神经元中活性氧（ROS）的总体减少有关。有趣的是，尽管有这种总体作用，美金刚并不能特异性降低转基因细胞中错误折叠的tau蛋白诱导的ROS水平。我们的数据表明，美金刚并不干扰错误折叠的tau蛋白诱导的特定病理途径，但仍能够减轻神经元中的氧化应激。
