基于髓鞘保护的活血通络法治疗阿尔茨海默病的作用机制研究

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment. There is currently no effective treatment. Chinese medicine believes that the pathogenesis of AD is mainly caused by qi deficiency and blood stasis, and toxic damage to the naoluo, and it should be treated by Yiqi Huoxue and Jiedu Tongluo. Studies have shown that the vulnerability of myelin in hypoxic and ischemic environment is the main cause and pathological phenotype of abnormal neural fiber network in early AD. Therefore, the maturation of myelin-derived oligodendrocytes is the key to repairing myelin damage and maintaining the integrity of nerve fiber bundles. Based on our preliminary work, this project will use magnetic resonance imaging technology combined with electron microscopy and molecular biology methods. Based on Dengzhan Shengmai capsule with the effect of Huoxue Tongluo, the protection of Huoxue Tongluo therapy on brain nerve fiber in AD transgenic mice will be studied. Its potential effect will be explored in regulating oligodendrocyte differentiation via RAS signaling pathway. The research will clarify the protective mechanism of Huoxue Tongluo on AD, and provide scientific basis for its clinical application.

阿尔茨海默病（Alzheimer’s disease, AD）是一种以认知障碍为主的神经退行性疾病，目前尚无有效治疗药物。中医学认为，AD病机以气虚血瘀、毒损脑络为主，治宜益气活血、解毒通络。已有研究表明，髓鞘在AD缺血低氧病理环境中的易损性，是AD早期神经纤维网络连接异常的主要原因及病理表型。因此，生成髓鞘的少突胶质细胞的成熟分化是修复髓鞘损伤和维护神经纤维束完整的关键。本项目在我们前期工作基础上，应用核磁共振成像技术结合电镜、分子生物学等方法，基于具有活血通络功效的灯盏生脉胶囊，研究中医活血通络法对AD转基因小鼠脑内神经纤维的保护作用，并探究其基于RAS信号通路调节少突胶质细胞分化的作用机制。本项目研究结果可阐明活血通络法治疗AD的作用机制，为其在中医临床应用提供科学依据。

阿尔茨海默病（Alzheimer’s disease, AD）是一种以认知障碍为主的神经退行性疾病，目前尚无有效治疗药物。中医学认为，AD病机以气虚血瘀、毒损脑络为主，治宜益气活血、解毒通络。已有研究表明，髓鞘在AD缺血低氧病理环境中的易损性，是AD早期神经纤维网络连接异常的主要原因及病理表型。因此，生成髓鞘的少突胶质细胞的成熟分化是修复髓鞘损伤和维护神经纤维束完整的关键。本研究基于具有活血通络功效的灯盏生脉胶囊，探究了中医活血通络法对AD模型鼠脑内神经纤维的保护作用。通过Morris水迷宫实验、硫黄素和尼氏染色，证明灯盏生脉胶囊治疗显著提升了AD大鼠认知能力，减少了老年斑的沉积，改善了AD病理损伤。通过核磁弥散张量成像分析发现，灯盏生脉胶囊保护了AD大鼠特定脑区神经纤维束完整性。电镜结果显示，灯盏生脉胶囊治疗后的AD大鼠大脑皮层髓鞘结构和功能均优于未经治疗的AD大鼠。进一步通过组化实验与蛋白组学分析，揭示了灯盏生脉胶囊通过调控少突胶质细胞PI3K-Akt-mTOR信号通路促进髓鞘生成，从而保护神经纤维束完整性的分子机制。该研究拓展了灯盏生脉胶囊的适应症，解析了灯盏生脉胶囊在AD中的脑保护作用机制，为其临床应用提供了科学依据；同时本研究系统使用现代科学技术从多角度阐明活血通络法治疗AD的作用机制，为中医药的推广提供基础。