基于肠道致病菌—Aβ靶点的新型抗阿尔茨海默症先导化合物—米仔兰属植物中特异性楝酰胺类衍生物的发现及作用机制研究

阿尔茨海默症（AD）是一种中枢神经系统退行性疾病，其神经元退变涉及多种病理变化，从而使单一靶点药物很难有效控制或治愈AD。肠道致病菌和β淀粉样蛋白（Aβ）在AD的发病中均起着关键性作用，而且肠道致病菌可通过脑—肠轴诱导Aβ的沉积。因此，肠道致病菌—Aβ可作为新型的分子靶点进行抗AD药物的研究与开发。. 本项目在已从米仔兰中发现了11种米仔兰属植物特征性、对5株肠道致病菌和Aβ25-35诱导的SH-SY5Y细胞损伤均具明显抑制作用的楝酰胺类新颖结构化合物基础上，拟对碧绿米仔兰和台湾米仔兰中的楝酰胺类成分进行定向分离和结构鉴定，并对该类化合物进行靶向肠道致病菌—Aβ活性筛选、构-效关系和作用机制研究，以期获得具有潜在药用价值的新型抗AD先导化合物。本课题的开展将为合理开发利用我国丰富的米仔兰属药植资源积累一定的资料，为肠道致病菌—Aβ抑制类抗AD药物的研发提供一定的科学依据。

Alzheimer's disease (AD) is a kind of degenerative disease of central nervous system. It is difficult to control or cure AD effectively based on the single-target drugs in that neurodegeneration is associated with many pathological changes. Enteropathogenic bacteria and the amyloid β (Aβ) protein play pivotal roles in the occurrence and development of AD. Moreover, enteropathogenic bacteria can led to the deposition of Aβ through the brain-gut axis. Therefore, enteropathogenic bacteria—Aβ can be used as a novel molecular target for the research and development of anti-AD drugs. . 11 Novel rocaglamide derivatives characteristic of the plants of the genus Aglaia, which exhibited potent inhibitory activities against five enteropathogenic bacteria and Aβ25-35-induced damage in SH-SY5Y cells, have been isolated from A. odorata in our previous experiments. This project will deal with the discovery of natural product-based on anti-AD agents from two plants of the genus Aglaia (A. perviridis and A. formosana) on the basis of these findings. The aim of this research is to search for characteristic rocaglamide derivatives from the Aglaia genus, to evaluate their enteropathogenic bacteria—Aβ inhibitory activities, structure-activity relationship, and mechanism of action of this type of compounds, and to obtain several novel lead compounds for new anti-AD drugs targeting enteropathogenic bacteria-Aβ. This research will be to afford more theoretic and experimental data for investigation of rich source of the Chinese Aglaia plants ande to provide certain scientific data for the discovery of new anti-AD drugs targeting enteropathogenic bacteria-Aβ.