乳酸调控阿尔茨海默病神经血管损伤的作用机制研究

Alzheimer’s disease is a neurodegenerative disease characterized by learning and memory impairment, which lacks of effective therapy in clinic. Epidemiological, imaging and pathological evidence showed that neurovascular dysfunction and lactate deficiency are two important pathological features of AD, but the correlation between them was not clear. The study of lactic acid on tumor blood vessels and peripheral blood vessels suggests that lactic acid has the potential to regulate neurovascular function, but the mechanism of lactic acid regulating neurovascular function remains to be studied. In this project, 5xFAD mice were used to clarify the correlation of lactate deficiency and neurovascular dysfunction with the increase of age. The crucial mechanism of lactic acid regulating neurovascular structure and blood-brain barrier function was elucidated by two intervention modes of lactic acid supplement and knocking down the expression of HCAR1 receptor, with the method of Micro-optical sectioning tomography and laser microdissection. Further more，the possibility of lactic acid as an efficacy marker for neurovascular therapy will be explored by studying the correlation between the lactic acid level and the efficacy of drugs. This project is a creative study on the relationship between lactic acid and neurovascular function in 5xFAD mice，which is expected to provide a new perspective and strategy for the treatment of AD.

阿尔茨海默症（AD）是以学习记忆障碍为主要临床特征的神经退行性疾病，迄今缺乏有效的治疗手段。流行病学、影像学和病理学证据表明神经血管功能障碍和乳酸缺乏是AD的两个重要病理特征，但两者的相关性并不清楚。乳酸对肿瘤血管和外周血管的研究提示乳酸具有调控神经血管功能的潜能，但乳酸对神经血管的调控机制尚待研究。项目以5xFAD小鼠为实验对象，明确乳酸缺乏和神经血管功能障碍随月龄增长的变化趋势和相关性。通过乳酸补充和敲低乳酸HCAR1受体表达两种干预模式，采用显微光学切片断层扫描和激光显微切割等手段，阐明乳酸调控神经血管结构和血脑屏障功能的关键机制。同时，通过研究血管靶向治疗中5xFAD小鼠体内乳酸水平和药物疗效的相关性，探索乳酸作为AD神经血管治疗药效监控指标的可行性。本项目在5xFAD小鼠模型上开拓性地研究乳酸与神经血管功能的关系，有望为AD治疗提供新的角度和策略。

阿尔茨海默症（AD）是以认知功能障碍和老年斑沉积为关键特征的神经退行性疾病，确切发病机制迄今尚不明确，因此也缺乏有效的治疗手段。已有文献报道AD重要的病理特征包括老年斑沉积、神经血管功能障碍、乳酸缺乏，然而三者相关性不明确并缺乏机制研究。本项目基于以上背景开展研究，并取得以下进展：1）应用AD转基因动物揭示了AD发病进程中乳酸、琥珀酸、丙酮酸、苹果酸等小分子代谢物的动力学变化特征，证实乳酸代谢障碍是AD病变过程的关键能量代谢障碍小分子；2）明确乳酸代谢障碍与AD神经血管功能障碍、行为学障碍的病变进程的关联性，证实乳酸代谢障碍发生在AD关键病理老年斑和胶质细胞增生之后，并发生在神经血管功障碍和认知/日常行为障碍起始阶段；3）证实乳酸干预可有效调控AD转基因动物能量代谢障碍、改善血管功能障碍和胶质细胞增生；4）证实神经血管功能干预小分子可有效调控AD转基因动物认知行为障碍和脑微血管形态损伤，有成为相关疗效监控分子的潜力。上述研究结果进一步揭示了乳酸障碍与AD神经血管功能障碍的关联性，并为新型抗AD干预策略的研发提供了重要线索和依据。