MST1在阿尔茨海默病神经元变性中的作用及机制研究

神经元变性是阿尔茨海默病（AD）的重要环节。Aβ经多种途径诱导细胞凋亡是其重要因素，缺乏关键靶点，机制不清。MST1与细胞凋亡密切联系。Aβ诱导细胞凋亡的信号分子也是MST1信号途径的重要下游调控分子。我们发现AD脑内MST1表达增加，Aβ增加MST1表达，抑制MST1改善Aβ诱导神经元变性。因此，我们提出MST1可能是Aβ毒性的一个关键分子，是早期防治AD的一个潜在靶点。本研究拟首先通过拓展的临床和动物研究，探讨AD的MST1变化特点及与AD关系，评价MST1对AD的早期诊断价值；然后通过离体实验观察Aβ对MST1蛋白表达的作用、调控MST1对细胞凋亡的影响、MST1对Aβ诱导细胞凋亡的作用；再探讨Aβ对MST1基因表达调控机制、Aβ作用下MST1对凋亡相关分子机制；最后探讨抑制脑内MST1表达对AD防治作用。本项目完成，有望深入揭示AD发生机制，为AD防治研究提供新靶点和重要科学依据。

Neuronal degeneration is an important link in Alzheimer's disease (AD). Apoptosis induced by Aβ is an important factor, lacking of key targets and unclear mechanism. MST1 is closely related to apoptosis. Signal molecules that induce apoptosis by Aβ are also important downstream regulators of the MST1 signaling pathway. We found that the expression of MST1 in the brain of AD increased, the expression of MST1 increased by Aβ, and the inhibition of MST1 improved the degeneration of Aβ induced neurons. Therefore, we suggest that MST1 may be a key molecule for Aβ toxicity and a potential target for early AD prevention. The purpose of this study was first to explore the changes of MST1 in AD and its relationship with AD through expanded clinical and animal studies, and to evaluate the value of MST1 in the early diagnosis of AD. Then experiments in vitro were conducted to observe the effect of Aβ on the expression of MST1 protein, the regulation of MST1 on apoptosis, and the effect of MST1 on Aβ-induced apoptosis. The regulation mechanism of MST1 gene expression by Aβ and the apoptosis-related molecular mechanism of MST1 under Aβ were discussed. Finally, the effect on the prevention and treatment of AD was discussed by inhibition of MST1 expression in brain. The completion of this project is expected to deeply reveal the occurrence mechanism of AD and provide new targets and important scientific basis for the prevention and treatment of AD.