EGFR通路信号因子介导Aβ42细胞毒性的分子机制研究

Alzheimer’s disease (AD) belongs to neurodegenerative diseases with high morbidity in aged people. Studies on the molecular mechanisms of AD onset proved that the abnormally aggregated amyloid-β 1-42 (Aβ42) peptides in neuronal system is one of the key factors for AD pathogenesis. However, it remains to be demonstrated that how differently the diverse Aβ42 forms function and which signalling pathway mediates the Aβ42’s cytotoxicity . In this project, we plan to begin our research by studying the effects of different Aβ42 aggregates on epidermal growth factor receptor (EGFR) pathway factors. This helps to explore the psychological functions of Aβ42 monomer, oligomer and fibril, respectively, at the molecular level. Then, we will use several inhibitors for the EGFR pathway factors in our study, and try to detect their anti-Aβ42 effects. With these data, we will be able to analyse whether and how these factors mediate the Aβ42-induced immunoreaction, cell apoptosis and mental retardation, and also the mechanisms' similarities and differences. Results of this project will not only enrich our knowledge about Aβ42’s cytotoxicity and AD pathogenesis, but also indicate new directions for designing and developing clinical AD drugs.

阿尔茨海默病 (Alzheimer’s disease, AD)是老年人群高发的神经退行性疾病。对疾病发生机制的研究认为神经系统内异常聚集的淀粉样蛋白Aβ42是关键的致病因子之一。但是当前对于Aβ42的不同聚集形态的生理功能差异以及介导Aβ42细胞毒性的分子信号通路仍然认识有限。本课题首先利用细胞生物学和分子生物学方法检测不同聚集形态的Aβ42对表皮生长因子受体（EGFR）通路信号因子的刺激效果，研究Aβ42的单体、寡聚体和纤维态三种主要聚集形态在分子水平上各自的作用特点。然后，检测多种EGFR通路信号因子的特异性抑制剂对寡聚体Aβ42细胞毒性的拮抗效果，可以进一步揭示出这些信号因子介导寡聚体Aβ42诱发炎症反应、细胞凋亡和认知功能障碍的分子机制及其异同性。课题研究成果不仅有助于深入认识Aβ42的细胞毒性作用和AD发生的分子机制，也为设计和开发临床药物提供新的思路。

淀粉样蛋白β1-42(Aβ42)被认为是导致阿尔兹海默病（Alzheimer’s disease, AD）发生的重要致病因子。前期的研究认为Aβ42通过激活表皮生长因子受体(EGFR)信号通路，引起转基因果蝇和转基因小鼠的认知功能障碍。在此基础上,本项目主要从三个方面继续深入进行：一是探索EGFR下游介导Aβ42神经毒性的关键信号因子，以及筛选潜在的治疗药物；二是探索Aβ42的神经毒性与物质代谢紊乱之间的联系；三是开发可用于早期疾病诊断的DNA单碱基突变检测技术。综合利用遗传学、药理学、分子生物学等技术，我们的结果显示AKT、PDK1和Rac1可能参与到Aβ42的神经毒性作用中，而相应的AKT和PDK1的抑制剂能够显著改善转基因果蝇的认知功能缺陷。通过以LC-MS为主的代谢产物分析和Q-PCR为主的基因转录水平分析，我们并未发现Aβ42的神经毒性和糖代谢紊乱之间具有显著相关性。借助于DNA短暂杂交、磁珠分离和全内反射显微成像等技术方法，我们设计开发了多种用于检测DNA单碱基突变的技术手段，相比现有方法在特异性和灵敏度上有较大提高。本项目的研究进展，对于深入认识阿尔兹海默病的发病机制，开发诊断和治疗方法具有积极的推动意义。