乙酰化tau蛋白对线粒体动态平衡的损伤及机制研究

The damage of mitochondrial dynamic plays an important role in the development of Alzheimer's disease (AD), as well as microtubule-associated protein(tau), and different types of post transcriptional modification microtubule-associated protein(tau) have distinct effects on mitochondrial homeostasis, however, the influence of acetylated tau protein on the mitochondrial dynamic is not clear. Our Preliminary results in AD transgenic mice (3xTg-AD) have shown that the acetylated tau protein were significantly increased, and they were increased in mitochondrial , which suggest that acetylated tau protein may take part in the abnormalities of the structure and function of mitochondrial. In the project we will upregulate the expression of acetylated tau in the cell lines, primary neurons and wild type mice, then investigate its effect on mitochondrial morphology, and explore the underlying molecular mechanism, at the same time, We will also investigate whether disturb the acetylation of tau attenuates mitochondrial damage, pathogic changes and cognitive deficits in 3xTg-AD mice. The results will firstly reveal the role of acetylated tau in the damage of mitochondrial dynamic and cognitive function in AD, which further clarify the development of AD and provide new strategy for treatment.

线粒体动态平衡的损伤在阿尔兹海默病（Alzheimer's disease，AD）的发生发展中发挥着重要作用，微管相关蛋白（tau）是AD重要的病理学标志，其不同类型的转录后修饰对线粒体动态平衡的作用各异，而乙酰化修饰的tau蛋白对线粒体动态平衡的影响尚不清楚。申请者最近的研究发现，在AD转基因鼠（3xTg-AD）中tau蛋白的乙酰化水平明显增高，且在线粒体中表达同样增高，关系密切，这提示AD中乙酰化的tau蛋白可能影响线粒体的结构和功能。本研究拟在细胞系、原代神经元和野生型小鼠中上调乙酰化tau蛋白，研究其对线粒体形态的影响，并深入探讨其中的分子机制，同时通过干扰tau蛋白的乙酰化，观察能否逆转线粒体的损伤及3xTg-AD小鼠的学习记忆障碍。研究结果将首次揭示AD中tau蛋白的乙酰化修饰对线粒体动态平衡和动物认知功能的损伤作用，进一步阐明AD的发生发展机制，并为后续的治疗提供新的思路。

线粒体动态平衡的损伤在阿尔兹海默病（Alzheimer's disease，AD）的发生发展中发挥着重要作用，微管相关蛋白（tau）是AD重要的病理学标志，其不同类型的转录后修饰对线粒体动态平衡的作用各异，而乙酰化修饰的tau蛋白对线粒体动态平衡的影响尚不清楚。申请者预实验发现，在AD转基因鼠（3xTg-AD）中tau蛋白的乙酰化水平明显增高，且在线粒体中表达同样增高，关系密切，这提示AD中乙酰化的tau蛋白可能影响线粒体的结构和功能。本研究提出乙酰化的tau会影响线粒体的动态平衡和线粒体生成，降低神经元的突触可塑性，增加神经元的凋亡。通过基因干扰tau蛋白的乙酰化，可以线粒体的损伤。并且发现通过靶向线粒体动态平衡和线粒体生成的药物治疗乙酰化tau蛋白导致的线粒体的损伤，可以改善神经元的突触可塑性，减少神经元凋亡，改善小鼠的学习记忆损伤。本项目将首次揭示AD中tau蛋白的乙酰化修饰对线粒体动态平衡和动物认知功能的损伤作用，进一步阐明AD的发生发展机制，并为后续的治疗提供新的思路。