解析高脂食物对阿尔茨海默症果蝇的影响及其脂质代谢相关的作用机制

Alzheimer’s disease is a neurodegeneration disease characterized clinically by progressively memory loss and behavior defect, which in the majority of cases occurs late of the life. The pathogenesis of Alzheimer’s disease is still not clear up to now. Lipids are the key regulation factors for normal function in brain. More and more evidences show there is a tight correlation between lipid and neurodegeneration disease like Alzheimer’s disease. For lipid analysis, lipidomics is a high throughput method to measure the quality and quantity of lipid and discover their changes and functions under different physiology or pathology conditions. Here we used lipidomic analysis and confirmed that the Alzheimer’s disease model is a creditable model for dissecting the pathogensis mechanism on lipid metabolism aspect. And we also showed that high fat diet exacerbated the pathogenesis of Alzheimer’s disease. We want to further to dissect the mechanism that how high fat diet affects Alzheimer’s disease in Drosophila. Though the data analysis of the full lipid profiles of Alzheimer’s disease on normal food and high fat diet, we want to find the lipid(s) which correlated to Alzheimer’s disease. We will verify the information we get from lipidomic analysis using genetic and biochemistry approaches. We will knock down (out) or overexpress the lipid(s) related enzyme(s) to see whether the phenotype of Alzheimer’s disease is affected. After that we will get the clue which lipid pathways involved into Alzheimer’s disease and provide more evidences to the prevention and mechanism investigation of Alzheimer’s disease.

阿茨海默症是老年人中多发的一种神经退行性的疾病，它主要临床症状是记忆力衰退，运动行为障碍。近年来虽然有许多关于阿尔茨海默症的报道出现，但是它的发病机理却并不清楚。脂类是大脑行使正常功能的关键调节因子，越来越多的证据表明脂类和包括阿茨海默症在内的许多神经退行性疾病相关。脂质组学是大规模定性和定量研究脂类并了解它们在不同生理病理条件下的功能和变化的方法学。利用脂质组学的方法我们确认了阿尔茨海默症果蝇模型是从脂代谢角度研究阿尔茨海默症的可行的动物模型。通过用不同浓度的椰子油食物处理阿尔茨海默症果蝇，我们看到高脂食物确实加剧了阿尔茨海默症果蝇的病理进程。本课题利用脂质组学方法在果蝇中解析高脂食物对阿茨海默症的影响，通过分析阿茨海默症果蝇的全脂图谱，找出与阿茨海默症相关的脂代谢通路，并结合体内的基因敲减及过表达实验和生化实验进行验证，从而为人类阿茨海默症的预防及机理的探究提供依据。

阿尔茨海默病是一种神经退行性疾病，它多发于老年人中。在患病的后期，病人生活不能自理，给患者家庭及社会带来了严重的精神和经济压力。本课题旨在利用阿尔茨海默病果蝇模型，研究高脂饮食是否影响阿尔茨海默病的病理进程。从实验结果我们可以看到高脂加剧了阿尔茨海默病果蝇的行动能力受损和认知障碍的的表型，使其生命周期明显变短。通过脂质组学的分析，我们可以看到内吞通路相关的脂类在高脂处理后发生的变化，这些变化暗示这阿尔茨海默病果蝇在高脂饮食状态下内吞通路受到了破坏。通过荧光观察，我们可以看到对对照组果蝇来说，高脂食物处理时期内吞标记物荧光信号增强，而高脂食物却不能是阿尔茨海默病果蝇体内的内吞信号发生变化，这就进一步证实了高脂食物处理下，阿尔茨海默病果蝇内吞通路受阻，不能正常的将有害的物质输出，从而在体内积累造成对机体的损伤，加剧了阿尔茨海默病的病理进程。