SIK2通过mTOR-HIF1通路调节小胶质细胞代谢重编程在AD病理进程中的作用

神经炎症与阿尔茨海默病（AD）的发生发展密切相关，而小胶质细胞代谢重编程决定了其功能表型并促进神经炎症的发生，但小胶质细胞代谢调控机制还不明确。SIK2是细胞代谢的重要调节基因，我们发现：SIK2主要表达于小胶质细胞；且在5×FAD转基因鼠海马脑区表达下调；敲减BV2细胞中SIK2，可激活mTOR-HIF1通路，并促进糖酵解关键酶基因的表达；因此我们推测SIK2通过mTOR-HIF1通路调节小胶质细胞发生代谢重编程介导AD病理进程。本项目将利用5×FAD：Cx3cr1Cre/SIK2fl/fl转基因鼠敲减或病毒注射过表达SIK2基因，观察其对AD鼠认知和小胶质细胞功能的影响；通过AAV病毒调控原代小胶质细胞SIK2基因表达，揭示SIK2通过mTOR-HIF1通路调节小胶质细胞发生代谢重编程，促使其向促炎表型的转化。本研究有助于阐明SIK2基因参与AD发病的机理，并为临床干预提供参考。

Neuroinflammation is closely related to the occurrence and development of Alzheimer's disease (AD), and metabolic reprogramming of microglia determines its functional phenotype and can promote the occurrence of neuroinflammation. However, the regulatory mechanism of microglia metabolic reprogramming is still unclear. SIK2 is an important regulatory gene of cell metabolism. Our results showed that SIK2 was low expressed in the hippocampus of 5×FAD transgenic mice and mainly expressed in microglia. Knockdown of SIK2 can activate the mTOR-HIF1 pathway and promote the expression of key glycolytic enzyme genes in BV2 cells; Therefore, we speculate that SIK2 regulates the metabolic reprogramming of microglia through the mTOR-HIF1 pathway and mediates the pathological process of AD. 5×FAD：Cx3cr1Cre/SIK2fl/fl transgenic mice and virus injection will be used to regulate the expression of SIK2 in microglia cells, which will clarify the effects of SIK2 gene on the cognition and microglia function in AD transgenic mice. AAV virus is used to regulate the expression of SIK2 gene in primary microglia. We will investigate whether SIK2 can mediate the metabolic reprogramming of microglia through the mTOR-HIF1 pathway and promote it conversion to a pro-inflammatory phenotype in vitro. This study is helpful to clarify the mechanism of SIK2 gene involvement in the pathogenesis of AD and provide reference for clinical intervention.