阿尔兹海默症（AD）是认知功能渐近性衰退疾病，我国有近千万患者但无有效药物。申请人发现tau缺失小鼠脑内出现AD样神经学病变，包括突触相关蛋白减少、脑萎缩、铁离子聚集等，行为学研究发现这些小鼠出现认知及记忆功能障碍，使用铁离子螯合剂可以改善tau缺失小鼠的脑萎缩及记忆损害程度（Nat Med2012；Mol Psychiatr2016）。突触可塑性是学习记忆的基础，而前额叶皮层是认知相关高级中枢，鉴于幼年tau蛋白缺失小鼠不出现学习记忆障碍，申请人希望制备时间可控的tau敲除小鼠，并活体长时程观察tau蛋白在敲除前后对前额叶皮层突触可塑性的调控，在精细环路水平明确tau蛋白对皮层功能的调控。同时，将使用药物干预的方法，在神经微环路结构水平探索保护策略，进行新药的初步筛选。拟通过以上研究明确tau蛋白在学习记忆相关神经环路中的生理作用并以此为靶点初步进行药物研发。

Alzheimer’s disease (AD) represents neurodegenerative disorders with cognitive impairment, which affects millions of Chinese without a cure. We found previously that mice that lack tau exhibited phenotypes of AD, including reductions of synaptic proteins, smaller brain, atrophy, and iron accumulation, which accompanied with cognitive behavioral deficits (Nat Med2012；Mol Psychiatr2016). These can be rescued by iron chelation therapy. Synaptic plasticity is the foundation of memory, and the brain region responsible is frontal cortex. Since young mice lacking tau displayed no cognitive loss (only the aged ones do), we proposed to prepare regional, inducible transgenic mice (overexpression or knockout tau), to investigate the potential function of tau in cortical circuits. We also propose to screen new compounds using the same model system. These information will help to understand the physiological function of tau in cortical circuits, and to develop new compounds for further testing.