Tau蛋白异常聚积在阿尔茨海默病（AD）学习记忆障碍的发生发展中起关键作用，但机制尚不清楚。前期研究发现：过表达tau40可见部分tau蛋白定位于线粒体上，线粒体直径变长和核周聚集、融合加快；CoxIV和TOMM20水平、mt-Atp6/Rpl13比值显著增加，TFAM和PGC-1αmRNA水平无差异；定位于线粒体上PINK1/Parkin水平下降。因此我们假设：tau蛋白使定位于线粒体上的PINK1蛋白减少，导致线粒体自噬障碍和功能受损，诱导神经元突触功能障碍和丢失，引起学习记忆缺陷。本项目拟在细胞系、原代神经元和转基因鼠重点探讨PINK1在tau过表达所诱导的线粒体自噬障碍中的关键作用，阐明tau过表达导致线粒体自噬障碍的机制；探讨上调PINK1对tau蛋白诱导的突触可塑性及行为学障碍的改善作用。本研究可能揭示tau诱导记忆损害的分子机制，为tau相关疾病的药物研发提供新分子靶点。

Abnormal accumulation of the microtubule-associated protein (tau) plays the key roles in the development of cognitive deficits in Alzheimer’s disease (AD), however, the mechanism is still not clearly understood. Our Preliminary data have shown that overexpression of human full-length tau induced tau localization in the mitochondria, and mitochondrial elongation and perinuclear accumulation accompanied with increasing mitochondrial fusion. The mitochondrial markers, CoxIV and TOMM20, and the ratio of mt-Atp6/Rpl13, which means relative levels of mito-DNA in one single cell, all increased after tau transfection. Moreover, the levels of PINK1 and Parkin localized in the mitochondria decreased. These data suggest that tau protein induced PINK1 localization in the mitochondria fraction decreased, and then, led to mitophagy deficits, cause mitochondria dysfunction, and induce spines lose and abnormal cognitive abilities. The project will study the key role of PINK1 in tau-induced mitophagy deficits, and investigate the molecular mechanisms of the decreased PINK1 localization in the mitochondria fraction, which induced by abnormal accumulation of tau, and study whether upregulation of PINK1 attenuates mitochondrial dysfunction, mitophagy and abnormal cognitive deficits in cell lines, primary cultured neurons and human tau (htau) transgenic mice. The results will disclose the mechanisms of abnormal mitophagy induced by Alzheimer-like abnormal accumulation of tau. The research not only has an important theoretical significance, but also provides new molecular targets for drug research and development of tauopathies.