TREM2调控神经免疫炎症参与晚发型AD（LOAD）中类淋巴系统清除Aβ功能的机制研究

Amyloid-β (Aβ) -mediated microglia (MG) inflammation cascade response is an important mechanism of neuronal damage in Alzheimer's disease (AD). As the disease progresses, there is a disorder in the intracranial Aβ clearance function. The continuously deposited Aβ brings AD into the vicious circle mode of neuroinflammation damage, ending the vicious circle and becoming the central link in the treatment of AD. Our previous studies have demonstrated that Aβ-mediated MG neuroinflammatory response can induce astrocyte to transform into A1 astrocytes and inhibit the expression of aquaporin 4 (AQP4) in this type of cell, leading to dysfunction of glymphatic system clears of Aβ based on AQP4 regulation. Depending on the above findings, we believe that the inflammatory regulatory gene TREM2, which is specifically expressed in MG, is expected to terminate the vicious cycle pattern of AD by regulating the immune response of MG and resetting the glymphoid system to clear Aβ. This project intends to identify the specific site of action and related mechanisms of TREM2 from multiple levels of animal, cell and molecular levels using virus overexpression and knockdown techniques, immunofluorescence, qPCR, western blot, and two-photon confocal in vivo imaging. Providing a new breakthrough for the treatment of AD.

淀粉样蛋白(Aβ)介导小胶质细胞(MG)炎症瀑布反应是阿尔茨海默病(AD)神经元损害的重要机制。随着病情进展，颅内Aβ清除功能出现障碍，不断沉积的Aβ将AD带入神经炎症损害恶性循环模式，终止恶性循环，成为治疗AD的中心环节。我们前期研究证实Aβ介导MG免疫炎症反应可诱导星形胶质细胞向A1型星形胶质细胞转化，并抑制该型细胞内足水通道蛋白4(AQP4)表达，导致基于AQP4调控的类淋巴系统清除Aβ功能障碍。基于上述研究发现，我们认为特异性表达于MG的炎症调控基因TREM2，有望通过调控MG免疫炎症反应，恢复类淋巴系统清除Aβ功能，以终止AD恶性循环模式。本课题拟从动物、细胞、分子水平多个层面，采用病毒过表达及敲减技术、免疫荧光、qPCR、western blot、双光子共聚焦活体成像等技术明确TREM2具体调控的作用位点及相关机制，为AD的治疗提供新的突破口。

淀粉样蛋白(Aβ)介导小胶质细胞(MG)炎症瀑布反应是阿尔茨海默病(AD)神经元损害的重要机制。有效清除颅内Aβ沉积，终止Aβ介导神经炎症损害恶性循环模式，有望成为治疗AD的中心环节。本项目发现1. 体外实验证实Aβ 引导M1 型MG 可诱导A1 型星形胶质细胞形成及其内足AQP4 蛋白表达功能下降；2.成功构建中老年高血压小鼠模拟LOAD模型；3.首次发现A1型星形胶质细胞存在于LOAD小鼠模型及A1型星形胶质细胞内足AQP4功能异常所致类淋巴系统功能障碍;4.离体实验证实TREM2可抑制小胶质细胞炎症反应并阻断A1 型星形胶质细胞生成，进而重塑及其内足AQP4 蛋白表达功能，且对神经元有明显保护作用。5.在体实验通过AAV立体注射递送TREM2发现可重塑星形胶质细胞AQP4颅内表达重定位，改善类淋巴系统清除功能，Aβ42沉积减少。研究结果扩展TREM2 在LOAD 更多作用位点及相关机制，为AD 的治疗提供有效的靶点，具有较好的转化医学价值。项目招收硕士研究生2名，均在读。项目发表SCI论文3篇。

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