阿尔茨海默病（AD）是一种严重危害老年人的致死性神经退行性疾病，发病率逐年升高，其发病机制未明。研究显示，AD脑内淋巴系统功能下降加速了AD病程进展，并与脑内有毒代谢产物互为因果，相互促进，形成一个恶性循环。申请人前期研究发现，小檗碱可通过抑制反应性星形胶质细胞增生和保护AQP4极化而促进AD小鼠脑内胶质淋巴系统对外源性Aβ的清除。而星形胶质细胞增生和AQP4极化率下降是导致AD脑内胶质淋巴系统功能下降的关键因素。因此，推测小檗碱可通过抑制星形胶质细胞增生、保护AQP4极化、促进脑膜淋巴管发育而改善AD脑内淋巴系统功能，发挥防治AD作用。本项目拟用双光子活体成像技术和CLARITY三维技术，利用三转基因小鼠，结合代谢组学等技术，明确小檗碱在改善AD脑内淋巴系统功能和抗AD的作用及其机制。本项目的完成将为深入理解小檗碱抗AD机制提供全新思维和视角。

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with high mobidity and motality. Its pathogenesis is yet to be identified. Studies have shown that the functional impairment of lymphatic drainage system in the brain of AD accelerates the progression of the disease courses of AD, and the toxic metabolites in the brain cause and effect each other and promote other, forming a vicious cycle. Previously, we have confirmed that berberine can promote the excretion of exogenous Aβ through the glymphatic system in AD brain by inhibiting reactive astrocyte proliferation and protecting AQP4 polarization. Interestingly, the reactive astrocyte proliferation and loss of AQP4 polarization is a key factor for the functional impairment of lymphatic drainage system in the brain of AD. Therefore, we speculate that berberine can improve the function of the lymphatic drainage system in the brain of AD by inhibiting the proliferation of astrocytes, protecting AQP4 polarization, and promoting the development of dural lymphatic vascular, thus playing a role in the prevention and treatment of AD. The study utilized varieties of technologies, including dual photon confocal microscopy in-vivo imaging, CLARITY 3D technology, APP /tau /PS1 mouse model of AD, hispathology, metabolomics, etc. We explore the effects of berberine on improving lymphatic drainage system function in the brain of AD. The completion of this project will provide a new perspective on understanding the mechanisms of berberine in protecting against AD.