Tau蛋白翻译后修饰方式异常和AD及其他Tau病的发生密切相关。而Tau蛋白异常聚集形成的细胞内的神经纤维缠结是AD疾病重要的病理特征之一。是否Tau蛋白的异常翻译后修饰驱动了接下来的异常聚集过程，目前还知之甚少。揭开Tau蛋白异常翻译后修饰和聚集的关系对于理解AD的发病机制具有重要的价值。本项目研究围绕各种翻译后修饰对Tau蛋白错误折叠和聚集的影响，首先结合多种实验手段如CD、NMR和ThT荧光实验从宏观上确定异常磷酸化、N-糖基化及乙酰化等修饰方式对Tau蛋白构象特征和聚集行为的影响，在此基础上采用多种增强采样的和多尺度分子动力学模拟方法结合马尔科夫状态模型、复杂网络分析等分析手段揭示几种修饰方式影响Tau蛋白错误折叠和聚集的分子机制。该项目的完成将为揭开由Tau形成的神经纤维缠结导致的AD及其他Tau病的分子机理奠定重要的理论基础，也为针对目前仍无药可医的AD的药物开发提供重要参考。

The abnormal post-translational modifications (PTMs) of Tau protein is closely related to the occurrence of AD and other Tau diseases. The formation of intracellular neurofibrillary tangles (NFTs) due to abnormal aggregation of Tau protein is one of the important pathological features of AD disease. Little is known about whether the abnormal PTMs of Tau protein drive the subsequent abnormal aggregation process. Uncovering the relationship between abnormal PTMs and aggregation of Tau protein is of great value in understanding the pathogenesis of AD. This study focus on the effects of various post-translational modifications on the misfolding and aggregation of Tau proteins. Firstly, we combined various experimental methods such as CD, NMR and ThT fluorescence experiments to determine the effects of abnormal phosphorylation, N-glycosylation and acetylation on the conformational characteristics and aggregation behavior of Tau protein macroscopically. Furthermore, we will apply the multiple enhanced sampling and multi-scale molecular dynamics simulation methods combined with Markov state model and complex network analysis to reveal the molecular mechanism of Tau misfolding and aggregation. The completion of the project will lay an important theoretical foundation for the molecular mechanism of AD and other Tau diseases caused by neurofibrillary tangles formed by Tau, and also provide an important reference for the development of drugs for AD, which has no medicine to cure at present.