突触损伤是阿尔茨海默病（AD）的早期病理表现之一，小胶质细胞介导的异常吞噬是导致突触受损的主要原因，但其机制尚不清楚。我们前期研究发现：在APP/PS1小鼠海马中Arid5a表达显著升高，采用特异性腺相关病毒抑制Arid5a可减轻突触损害，改善APP/PS1小鼠的认知功能。本课题将采用小胶质细胞Arid5a特异敲除AD小鼠（APP/PS1;Cx3cr1-Arid5af/f）及APP/PS1小鼠，进行以下研究：1）明确Arid5a介导AD模型小鼠认知下降及突触损害的作用；2）阐明Arid5a促进小胶质细胞过度修剪突触；3）揭示Arid5a通过结合补体C3受体的3’ 非编码区（C3R 3'UTR）调控小胶质细胞过度修剪突触的机制。本课题通过揭示来源于小胶质细胞的Arid5a加重AD早期突触受损的分子机制，为AD研究提供新的理论基础，为减缓AD早期突触损伤提供新的治疗靶点。

Synaptic damage is one of the early pathological manifestations of Alzheimer's disease (AD). Abnormal phagocytosis mediated by microglia is one of the main causes of early synaptic damage in Alzheimer's disease (AD). However, the mechanism of synaptic damage in the early stage of AD has not yet been clarified. Our previous data have shown that the expression of Arid5a in the hippocampus of APP/PS1 mice was significantly increased. Adeno-associated virus mediated Arid5a inhibition could improve the cognitive function of APP/PS1 mice and reduce synaptic damage. In this project, the Arid5a specific knockout in microglial of AD model mice APP/PS1; Cx3cr1-Arid5af/f and APP/PS1 mice will be performed for the following research: 1) to confirm the role that Arid5a mediates cognitive decline and synaptic damage in AD mice; 2) to clarify the correlation between Arid5a and the excessive synapse pruning by microglia; 3) to reveal the mechanism that Arid5a regulates the role of microglia on excessive synapse pruning through binding to the 3'UTR (untranslated regions, UTR) of C3R. This study reveals the molecular mechanisms of microglia-derived Arid5a aggravating synaptic damage in early stage of AD, which provides a new theoretical basis for the pathological mechanisms of AD, and provides new targets for the treatment of AD in early stages.