基于Akt/mTOR/70S6K通路雷公藤甲素调控自噬防治Alzheimer病机制的研究

近期研究指出自噬参与了Aβ沉积及阿尔兹海默病(AD)的发病，因此调控自噬逐渐成为研究AD的重要方向，而Akt/mTOR/70S6K作为抑制自噬的经典途径被广泛关注。尽管众多实验都证实雷公藤甲素(TP）具有神经保护作用，但其对AD病程中Aβ代谢及神经损伤的修复机制尚未阐明。课题组前期发现TP可以改善Aβ造成的神经损伤、减少自噬，且此作用可被Akt/mTOR/70S6K途径抑制剂雷帕霉素阻断，据此提出 “TP通过激活Akt/mTOR/70S6K途径抑制自噬调节Aβ代谢并进而修复神经损伤，改善AD的认知障碍” 的假说。拟以APP/PS1痴呆小鼠及Aβ处理的海马神经元为对象，基于Akt/mTOR/70S6K途径对自噬的调节，从在体和离体层次阐明TP防治AD的机制，明确TP修复AD神经损伤的具体靶点，充实传统医药理论，并为临床开发TP治疗AD提供科学依据，对缓解AD患者造成的社会压力起到积极作用。

Current evidence has shown that autophagy is critical for the pathogenesis of Alzheimer’s disease (AD) and the deposition of β-amyloid protein (Aβ). Therefore, autophagy has been the direction of research in AD in recent years. And accumulating evidence has shown that protein kinase B/ mammalian target of rapamycin/ ribosomal protein S6 kinase (Akt/mTOR/70S6K) signal transduction pathway is a classic pathway related to the regulation of autophagy. Triptolide (TP) has been shown to possess a broad biological profile including neurotrophic and neuroprotective effects. However, little is known about the mechanism of TP on Aβ metabolism and cytotoxicity of AD. Our preliminary experiments showed that TP could protect PC12 against Aβ-induced cytotoxicity and attenuate Aβ-induced PC12 apoptosis. In addition, TP could also suppress the level of autophagy. Therefore, in this study, we speculate that “TP will repair the neurological damage and cognitive impairment of AD through activating the Akt/mTOR/70S6K signaling pathway”. We plan to prove our hypothesis in animal and cell levels. Then we detect the effect and mechanism of TP in process of amyloid-peptide metabolism, also the mechanism on learning and memory of Alzheimer’s disease mice based on the autophagy regulated by the Akt/mTOR/70S6K signaling pathway. The results may provide an interesting view of the potential application of TP or TWHF in future. More importantly, it is hoped that this research can enlighten a new possible drug target of AD.