近年，将AD称为“3型糖尿病”的观点备受关注，AD与脑糖代谢及能量代谢等密切相关，从参与糖代谢调节的分子中探寻AD防治途径成为AD研究新策略。本课题组前期研究发现参与糖代谢调节的成纤维细胞生长因子21（FGF21）能有效改善AD大鼠学习记忆功能障碍、海马组织病理改变和ATP异常，缓解神经元损伤，FGF21可能通过调节脑能量代谢发挥防治AD作用，其具体作用途径和分子机理亟待阐释。本项目首先在动物和细胞水平确证FGF21防治AD的生物学功能，同时考察FGF21对脑能量代谢的影响；进一步分析神经元和星形胶质细胞中参与FGF21功能的受体及辅因子，同时探讨FGF21调节神经元能量代谢的直接和间接途径：神经元自身能量代谢途径和星形胶质细胞介导的能量交互调控，发现其中关键调控分子并确证其在介导FGF21功能中的地位。从脑能量代谢角度阐释FGF21防治AD机理；为防治AD的潜在靶点提供实验和理论基础。

In recent years, growing evidence suggests that brain glucose and energy metabolism is associated with AD, the latter of which has even been considered as type 3 diabetes. It prompted us to search for new therapeutic approaches for AD based on molecules involved in regulating glucose metabolism. In our previous study, we have found the amelioration effect of FGF21 on learning and memory dysfunction, neurodegenerative changes and abnormal ATP level in the hippocampus in rat models of AD, and FGF21 can protect neurons against cytotoxicity. These results suggested that the effect of FGF21 in brain energy metabolism may be a key aspect involved in the prevention and treatment of AD by FGF21, but the mechanism is unclear. In this project, first we will perform experiments that will further confirm the biological function of FGF21 in the prevention and treatment of AD at the animal and cellular levels, and observe the effect of regulation of brain energy metabolism by FGF21; then we will analyze the receptor and cofactor of neuron and astrocyte involved in the biological function of FGF21, and explore the direct and indirect pathways involved in the regulation of brain energy metabolism by FGF21: neuronal metabolism and astrocyte-neuron metabolic cooperation, and we will clarify the roles of the key regulatory molecules in the biological function of FGF21. The aim of this project is to clarify the mechanism of brain energy metabolism in the treatment of AD by FGF21 and provide new experimental evidence for the potential targets of FGF21 treatment of AD.