铝可引起认知功能障碍等中枢神经系统毒性，是AD发病的危险因素。Tau 蛋白异常高磷酸化组成的神经纤维缠结是AD和铝暴露引起神经器官病变的标志。蛋白磷酸酶PP2A是介导异常磷酸化Tau去磷酸化最活跃的酶，研究表明PP2A酶的调节亚基B存在着不同的异构体和表达组织特异性，进而导致PP2A在不同信号转导中功能的多样性。而有关铝诱导Tau磷酸化和PP2A是通过哪些亚基参与调控Tau磷酸化的功能研究不清。因此，本研究拟构建PP2A亚基缺失的细胞模型和海马细胞特异性ppp2r1a基因敲除小鼠，探讨PP2A及其亚基在铝诱导Tau蛋白异常磷酸化的作用机制；进一步以该通路为靶点，探讨芬戈莫德（FTY720）是否通过激活PP2A信号通路来缓解铝诱导的神经毒性。以期为明确铝毒性通路中的关键事件以寻找早期分子标志物，为FTY720临床治疗铝中毒应用提供理论基础。这对于重金属污染防治具有重要的科学价值和临床意义。

Aluminum can cause cognitive dysfunction and central nervous system toxicity, which is a risk factor for AD. Abnormally high phosphorylation of Tau protein can form the Neurofibrillary tangles which were be considered as the markers of nervous system lesions caused by AD and aluminum exposure. Protein phosphatase 2A is the most active enzyme that mediates the dephosphorylation of high phosphorylation of Tau protein. Studies have shown that the regulatory subunit B of PP2A enzyme has different isomers and tissue specificity of expression, which leading to the functional diversity of PP2A in different signal transduction. However, it is not clear about which subunits of PP2A regulate the phosphorylation of Tau protein induced by aluminum. So in this study we will construct cell models of PP2A subunit deletion and hippocampal cell-specific ppp2r1a knockout mouse models to explore the mechanism of PP2A and its subunits in the abnormal phosphorylation of Tau protein induced by aluminum.And we will further investigate whether the FTY720 alleviate the neurotoxicity induced by aluminum through by activation of PP2A signaling pathways. This research will contribute to identify the key events in the aluminum toxicity pathway and to find early molecular markers, which will provide a new strategy for the clinical treatment of neurotoxicity induced by aluminum and also to provide a theoretical and experimental basis for FTY720 clinical application.