基于神经元能量代谢及其依赖星形胶质细胞的能量交互调控研究FGF21防治AD机理

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.

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。

基于将阿尔兹海默病（AD）称为“3型糖尿病”的观点，课题组从参与糖代谢调节的分子中探寻AD防治的新策略，在前期研究中发现成纤维细胞生长因子21（FGF21）可能具有防治AD的潜力，但其对AD具体作用及机理亟需进一步研究。本项目首先采用包括APP/PS1转基因小鼠、Aβ诱导AD大鼠等不同动物模型及神经细胞AD样损伤模型，确证了FGF21对AD样病变的缓解作用；进一步，分析了与FGF21功能相关的受体和辅因子及其下游分子途径情况，确证了受体FGFR1参与介导FGF21发挥改善AD样病变的功能，发现神经元胞内下游途径PP2A/MAPKs/HIF-1α在FGF21缓解AD样神经元异常中发挥重要作用。同时，本项目分析FGF21对神经元能量代谢的影响，深入探讨FGF21调节神经元能量代谢的具体分子途径，明确了星形胶质细胞-神经元乳酸穿梭途径在FGF21保护神经元中的关键地位，于动物和细胞水平发现并确证了星形胶质细胞-神经元乳酸穿梭途径中关键调控分子MCTs在FGF21发挥相关功能中扮演重要角色。在完成上述项目原定计划并取得研究结果的基础上，本项目还于动物和细胞水平考察FGF21对MPTP导致神经元PD样损伤的作用，发现FGF21对PD模型中神经元损伤的保护作用，结合已有研究结果，更全面的揭示了FGF21在AD、PD等神经退行性疾病防治方面的潜在研究及应用价值。.本项目明确FGF21在防治AD、调节脑能量代谢方面的生物学活性，揭示受体、神经元胞内下游途径及星形胶质细胞-神经元乳酸穿梭途径中参与FGF21活性发挥的关键分子；从脑能量代谢角度阐释FGF21防治AD机理，为防治AD等神经退行性疾病的潜在靶点提供实验和理论基础。通过本项目，已发表论文11篇（SCI论文6篇），参加国际学术交流1次，培养研究生4名，协助培养研究生2名。