人参皂苷Rg1及其代谢产物原人参三醇通过调节Tau蛋白磷酸化和聚集改善学习记忆

Alzheimer's disease (AD) is a cognitive dysfunction disease, which serious threat human health. And there is a lack of effective treatment drugs. Ginsenoside Rg1, the active monomer of traditional Chinese medicine ginseng, has the function of improving cognition. Protopanaxatriol (Ppt), a metabolite of Rg1, has the advantages of lower molecular weight, better fat soluble and stronger permeability of blood-brain barrier, was found similar activity to Rg1 in preliminary study by our group. However, the mechanisms were unclear. In addition, recently research found that the major reason of cognitive decline and memory loss of Alzheimer’s disease patients was Tau pathology. Therefore, this project intends to study the mechanisms of Ppt and Rg1 improving learning and memory comprehensively and systematically in the level of the molecular, cellular and whole animal, using tau transgenic model and okadaic acid toxicity model to simulate tau pathology, using tau abnormal phosphorylation and Tau aggregation to be the breakthrough point, using kinds of methods such as transmission electron microscopy (TEM), visualization of fluorescence and flow cytometry. This project will identify the differences of activity and mechanisms between Ppt and Rg1 in improving learning and memory, provide data support for them to be new anti-AD drugs, and provide scientific evidence for the explanation and clinical application of the intelligence function of Chinese herbal medicine ginseng.

阿尔茨海默病(AD)是一种严重威胁人类健康的认知功能障碍性疾病，目前极度缺乏有效治疗药物。传统中药人参的活性单体人参皂苷Rg1具有改善认知的作用。本课题组前期研究发现，具有分子量低、脂溶性好、易透过血脑屏障优势的Rg1代谢产物原人参三醇(Ppt)，也具有提高认知的作用。但是二者的作用机制并不十分清楚。最新研究认为，Tau病变是AD患者认知衰退和记忆丧失的最重要原因。因此，本项目拟采用Tau转基因模型和冈田酸毒性模型模拟Tau病变，以Tau异常磷酸化和Tau聚集为切入点，采用电镜、荧光可视化、流式细胞术等方法，从分子、细胞和整体动物水平，系统研究Ppt和Rg1改善学习记忆的机理。本项目将确定Ppt、Rg1提高认知功能的活性差异和具体靶标，为将其开发为抗AD新药提供数据支持，同时也为中药人参“益智作用”的阐释和临床应用提供科学依据。

阿尔茨海默病（AD）目前极度缺乏有效治疗药物。传统中药人参的活性单体人参皂苷Rg1具有改善认知的作用。本课题组前期研究发现Rg1代谢产物原人参三醇(Ppt)，也具有提高认知的作用，但是二者的作用机制并不十分清楚。本项目通过三年的研究，已经按照计划完成申请书中的研究内容，研究表明Rg1及Ppt在细胞水平均可改善OKA所致的细胞损伤，在动物水平具有改善认知功能的作用。对Rg1及Ppt在Tau病理中的研究表明，二者均可改善Tau的异常磷酸化；Tau-BiFC荧光可视化技术表明二者对Tau的异常聚集也有明显的抑制效果；轴突的兴奋性谷氨酸受体及线粒体定位的检测，表明Rg1及Ppt不仅能改善常规AD样病变造模剂OKA引起的谷氨酸受体和线粒体在轴突上的定位障碍，而且对两种Tau突变直接造成的异常磷酸化进而引起的轴突定位障碍亦具有改善作用。提示我们Rg1及Ppt改善学习记忆的机理可能通过抑制Tau蛋白异常磷酸化和Tau聚集发挥作用，且二者均可调节Tau蛋白异常磷酸化引发的早期神经元功能障碍，本研究的实施为开发Ppt及Rg1做为促智新药提供数据参考，并为阐释中药人参的“益智作用” 提供理论支持。