阿尔兹海默症（Alzheimer's disease, AD）是严重威胁人类健康的神经退行性疾病。在AD患者脑中，Tau蛋白含量异常升高，且能介导Abeta蛋白的神经毒性。目前研究表明,降低Tau蛋白水平能够减少Abeta的毒性，并减少Tau的聚集。因此，降解细胞内Tau蛋白是治疗AD的新靶标和潜在策略。本项目针对Tau蛋白结构中无催化活性中心，难以设计抑制剂的特点，拟采用两种策略降解细胞内的Tau蛋白。策略一，通过增加Tau蛋白泛素化水平从而激活泛素-蛋白酶体系统；策略二，模拟蛋白错误折叠状态从而激活蛋白质量控制系统。分别设计活性分子，以期通过激活细胞自身的蛋白降解系统，实现特异地、可控地降解细胞内的Tau蛋白。设计开发新型可特异性识别并降解细胞内Tau蛋白水平的化合物。本项目研究不仅可为AD的治疗提供新的策略，也为调控疾病相关非酶蛋白含量的研究提供参考。

Alzheimer's disease (AD) is a devastating neurodegenerative disease.Tau protein is abnormally elevated in brains of patients with AD, and mediate the cytotoxicity of Abeta. Recent studies have shown that partial or complete knockout of tau can ameliorate the neurotoxicity caused by Abeta, and reduce tau aggregation. Therefore,partial degradation of intracellular tau protein would be a potential strategy for the treatment of AD.In this propopal, we plan to apply two different strategies to degrade tau, which has nonenzymatic activities. The first strategy is to activate ubiquitin-proteasome system by increasing the ubiquitination of tau. The second strategy is to activate the protein quality control system by imitating misfolded proteins. We will design and synthsize the molecules by these two strategies to activate the protein quality control system to specifically and controllably degrade intracellular tau protein. The design and development of novel compounds to specifically recognize and degrade intracellular tau, not only provide a novel strategy for the treatment of AD, but also provide a method to regulate the level of disease-related non-enzymatic proteins.