在阿尔茨海默氏病中异常高磷酸化的tau蛋白聚集形成神经纤维缠结，迄今为止哪个磷酸化位点是最好的药物靶点以及最终导致神经退行性变的机制尚不清楚。体外数据显示mTOR在Ser214、Thr231和Ser356位点直接磷酸化tau。本研究采用死后AD大脑来显示mTOR是否与ptauSer214、Thr231和Ser356相互作用。我们将用HEK293细胞来转染Ser214/T231/Ser356三个位点突变体，运用这些细胞系去证实磷酸化(p)/非磷酸化(Np)tau突变是否调控tau蛋白的生成和聚集，微管蛋白的稳定性，以及其是否破坏线粒体分裂融合动态和功能。进一步将携带tau突变的腺病毒注入小鼠脑中去研究其对认知功能的影响及如何在体内影响线粒体分裂融合动态和功能，以及rapamycin是否能挽救其在AD神经退行性变中的作用，这将为tau诱导的退行性变和病理改变提供分子基础。

Abnormally hyperphosphorylated tau aggregates form neurofibrillary tangles in Alzheimer disease (AD), however, it is still unclear which sites of tau phosphorylation would be the best drug targets and the cellular mechanism causes neurodegeneration is poorly understood. In vitro data showed that the mammalian target of rapamycin (mTOR) directly phosphorylated tau at Ser-214, Thr-231, and Ser-356. In the present study, we employed post-mortem human AD brain to show if mTOR was localized within p-tau at Ser-214, Thr-231, and Ser-356. We will develop different genetic variants of tau mutations at Ser-214, Thr-231, and Ser-356 using HEK293 cells as background, in these cellular systems, we not only confirmed if phosphorylated (p-)/-non phosphorylated (Np-) tau mutations mediate tau synthesis and microtubule stability but also found if that disrupted mitochondrial dynamics and functions. In vivo we further infused AAV carrying tau mutations into mice brain, we identified how three phosphoepitopes of tau mutations at Ser-214, Thr-231, and Ser-356 affect learning and memory， mitochondrial dynamics and functions，as well as how does rapamycin rescue cognitive deficits and ameliorates mitochondrial dysfunctions. Taken together, our data presented here provide a molecular basis for the tau-induced degeneration and pathology, meanwhile demonstrate that tau mutations by mTOR directly-mediated increases tau synthesis, decreases microtubule stability and disrupted mitochondrial dynamics and functions, which provides new insights into the molecular mechanisms underlying tauopathies.