基于金钗石斛生物碱调节细胞自噬的抗阿尔茨海默病机制研究

项目名称： 基于金钗石斛生物碱调节细胞自噬的抗阿尔茨海默病机制研究

项目编号： No.81473201

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 石京山

作者单位： 遵义医科大学

项目金额： 70万元

中文摘要： 阿尔茨海默病(AD)在老年疾病谱中的地位日益重要，目前尚缺乏有效治疗药物。近年来发现自噬功能减弱导致沉积的Aβ、异常Tau蛋白及受损细胞器不能及时清除是诱发AD的关键病因之一，但是否可通过调节自噬改善AD仍不甚清楚。我们前期发现金钗石斛生物碱可通过促进自噬发挥抗AD的作用，但详细机制不明。本项目拟进一步探讨不同月龄APP/PS1转基因AD小鼠自噬及学习记忆功能与Aβ沉积、Tau蛋白磷酸化等病理改变的相关关系，考察海马及皮质AMPK/Sirt1、NF-κB/相关炎症因子、Nrf2/抗氧化酶等信号通路的变化，以自噬诱导剂二甲双胍和自噬抑制剂羟氯喹为正反对照，从调控自噬的角度探讨金钗石斛生物碱改善APP/PS1转基因AD小鼠学习记忆功能的详细机制，为金钗石斛生物碱用于AD的治疗提供实验依据，并为基于调节自噬的AD治疗新策略打下基础。

中文关键词： 阿尔茨海默病；自噬；金钗石斛生物碱

英文摘要： The prevalence of Alzheimer's disease (AD) gets increasingly prominent in elderly people, but there is still lack of effective drugs for the treatment of AD. Recently, some studies suggest that decrease in autophagy results in deposition and accumulation of Aβ, abnormal tau protein, and damaged organelles, which is critical in the pathogenesis of AD. However, whether the drug can ameliorate AD via autophagy remains unclear. Our previous research has demonstrated that dendrobium nobile lindl alkaloids (DNLA) ameliorates AD in APP/PS1 transgenic mice through upregulation of autophagy. The present study aims to investigate the relationship between autophagy and the function of learning and memory, as well as pathological changes such as Aβ deposition and tau phosphorylation in APP/PS1 transgenic AD mice of different ages (month). Also, the various inflammatory pathways including AMPK/Sirt1, NF-κB/cytokines and Nrf2/antioxidase were examined. Utilizing autophagy inducer metformin and autophagy inhibitor hydroxychloroquine as positive and negative control respectively, the effects and the molecular mechanisms of DNLA on autophagy as well as learning and memory function of APP/PS1 transgenic mice were investigated. This project will provide pharmacological basis for application of DNLA into the treatment of AD, and offer new sights for designing autophagy-based AD treatment strategies.

英文关键词： Alzheimer's disease;autophagy;alkaloids of Dendrobium nobile