Tau蛋白异常导致学习记忆损害的分子机制研究

项目名称： Tau蛋白异常导致学习记忆损害的分子机制研究

项目编号： No.81471303

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘恭平

作者单位： 华中科技大学

项目金额： 70万元

中文摘要： Tau蛋白在细胞内异常聚积损害学习记忆功能。然而，tau是一种细胞骨架蛋白，对其损伤记忆的机制尚不清楚。申请者最近发现：过表达tau导致胞核中特定位点磷酸化的tau聚积，同时，10个转录因子水平有显著变化，其中，STAT1（信号转导及转录激活蛋白1）的转录活性升高到7.6倍；采用凝胶迁移实验证实了STAT1活性升高。由于STAT1升高与突触蛋白NR1/2B水平负相关，且负性调节学习记忆功能，我们推测，特定位点磷酸化tau蛋白在胞内聚积可能通过上调STAT1活性，抑制突触或/和记忆相关靶基因表达，从而损害学习记忆功能。本项目拟通过基因转染、行为学、电生理等技术，在细胞和小鼠整体水平探讨特定位点磷酸化tau蛋白是否通过上调STAT1的活性而损伤学习记忆，并阐明相关分子机制。研究结果可能发现骨架蛋白tau的新功能，揭示tau损害学习记忆的分子机制，并为保护tau相关疾病的认知功能提供新分子靶标。

中文关键词： tau蛋白；阿尔茨海默病；学习记忆；认知障碍

英文摘要： The intracellular accumulation of abnormal tau protein induced learning and memory deficits. Tau is a cytoskeleton protein, however, the underlying mechanisms of memory deficit induced by tau is still unclear. The applicants found that overexpression of tau induced the site-specific phosphorylation of tau accumulated in the nucleus. Moreover, the activities of 10 transcription factors had a significant change, especially, the activity of signal transducer and activator of transcription-1 (STAT1) increased to 7.6 fold compared with the control while tau overexpression. The increased STAT1 activity was also proved by gel shift assay. Recently, studies have reported that STAT1 negatively regulated the cognitive ability, and there was a cognitive correlation between STAT1 protein level and synaptic protein NR1/NR2B levels. Above all, the applicants speculated that the intracellular accumulation of abnormal tau protein may activate STAT1 to inhibit the expression of synaptic/memory-related proteins and impair the learning and memory functions. The purpose of this project is to investigate whether learning and memory impairment induced by the site-specific phosphorylation of tau is through activating STAT1, and its underlying mechanisms in the cell lines and mouse models by gene transfection, behavior tests and electrophysiology, and so on. The results will be helpful to discover the new function of tau, and reveal the molecular mechanisms of the learning and memory deficits induced by the abnormal accumulation of tau protein. The results will also provide new molecular target for protecting against tau-related cognitive deficits.

英文关键词： tau;Alzheimer's disease;learning and memory;cognitive deficits