FLT1介导神经元APP内吞和Aβ生成在阿尔兹海默病中的作用及分子机制研究

阿尔兹海默病（AD）是一种危害严重的神经退行性疾病，深入研究AD的分子机制，积极探索新的治疗靶点具有重要的医学及社会意义。申请者前期研究发现，酪氨酸激酶FLT1通过上调APP-Y682的磷酸化，显著促进细胞APP内吞和Aβ多肽的分泌，推测该过程是诱导AD发病的关键环节；为进一步研究，申请者设计、合成并筛选出了FLT1激酶的高特异性小分子抑制剂MZH17。在此基础上，申请者拟通过本项目着力解决以下科学问题：（1）FLT1对APP的磷酸化的作用方式；（2）APP-Y682的磷酸化在细胞膜上调节内吞的分子机制；（3）APP-Y682的磷酸化在内涵体中参与APP水解的调控机制。基于以上分子机制的研究结果，申请者拟评估FLT1作为AD新药靶点的可行性。

Alzheimer's disease (AD) is a serious neurodegenerative disease. It is of great significance to delve into the molecular mechanisms of Alzheimer's disease and explore new therapeutic targets. Our previous study demonstrated that tyrosine kinase FLT1 promotes APP endocytosis and Aβ polypeptide secretion by up-regulating the phosphorylation of APP-Y682. We infer that this is the crux of the induction of Alzheimer's disease. To further investigate this issue, we designed, synthesized and then screened a highly specific small molecule inhibitor of FLT1 kinase, MZH17. The objectives of the present study are to elucidate the following questions: (1) How FLT1 mediates phosphorylation of APP; (2) How phosphorylation of APP-Y682 regulates endocytosis as a cell membrane protein; (3) How phosphorylation of APP-Y682 participates in APP hydrolysis in endosomes. Finally, based on the above molecular mechanism research, we intend to evaluate the feasibility of FLT1 as a new drug target for AD.