基于AMPK下游通路探讨淫羊藿有效成分治疗AD的作用机制

The pathogenesis of Alzheimer’s disease (AD) is still unclear, and disease-modifying therapies for AD remain a major unmet medical need. According to the traditional Chinese medicine theory, “kidney governs the brain and the intelligence, whereas kidney-deficiency impairs brain functions and compromises intellectual capabilities”. Epimedium is a tonifying kidney-yang traditional Chinese medicine. Our previous studies have shown that icaritin (ICT), an effective component of Epimedium, exerts anti-AD effects via activating AMPK and inhibiting BACE1. The AMPK/PPAR-γ/PGC-1α pathway is a key metabolic pathway, which is involved in the pathogenesis of AD and the regulation of BACE1. Here we hypothesize that Epimedium may regulate BACE1 through the AMPK/PPAR-γ/PGC-1α pathway to modify the pathological changes in AD. To assess the current hypothesis, this project will study the effects of ICT on AD in APP/PS1/Tau triple-transgenic AD mouse model, and investigate the impacts of ICT on AMPK/PPAR-γ/PGC-1α pathway and BACE1 in AD mice. Moreover, the mechanism of how ICT regulates BACE1 and AMPK/PPAR-γ/PGC-1α pathway will be analyzed using gene silencing technology in vitro. In sum, this study will lay a foundation for the use of ICT for the treatment of AD, and provide a new theoretical basis for the therapeutic development of Epimedium.

阿尔茨海默病（AD）由于发病机制不明，缺乏有效的治疗药物。中医理论认为“肾主智，肾虚则智不足”，淫羊藿为补肾阳的中药，我们研究发现其有效成分淫羊藿素（ICT）具有抗AD作用，可激活AMPK，抑制BACE1。而AMPK下游通路与AD密切相关，且作为能量代谢的重要通路参与对BACE1的调节。据此，我们推测ICT通过AMPK下游通路调节BACE1活性，从而延缓AD的病理改变。本项目拟首先采用APP/PS1/Tau三转基因AD模式小鼠验证ICT对AD的作用，进而检测ICT对AD小鼠AMPK下游的主要通路（AMPK/PPAR-γ/PGC-1α通路）和BACE1的影响，最后应用基因沉默技术在离体实验中分析ICT通过AMPK下游通路调节BACE1抗AD的作用机制。本研究将为ICT用于治疗AD奠定基础，也为淫羊藿的开发提供新的理论依据。

阿尔茨海默病（Alzheimer's disease，AD）是目前老年人常见神经退行性疾病，以认知功能障碍为主要临床表现，造成严重的社会和家庭负担。淫羊藿素（icaritin, ICT）是从淫羊藿中提取的脂溶性黄酮类小分子化合物，具有治疗AD的潜力。本研究从体内、体外两方面验证ICT抗AD效应，并分析ICT对AMPK/PPAR-γ/PGC1-α通路调节作用。我们的研究结果发现：ICT对APP/PS1 AD模式小鼠认知功能有改善作用，并从体内外实验两方面明确ICT对AMPK/PPAR-γ/PGC1-α通路的调节作用；但同时，本研究也发现AMPK并非ICT的直接靶蛋白；ICT对AD小鼠改善作用也不能完全经由AMPK下游PPAR-γ/PGC1-α通路解释；我们还发现ICT促进寡聚体向淀粉样斑块转变，促进小胶质细胞向斑块迁移；上述现象是否是通过AMPK蛋白调控仍需进一步研究；此外，我们发现ICT对AD模型小鼠自噬通路相关蛋白有显著影响，能够调节TDP-43影响线粒体功能。总之，本项目研究为ICT的开发提供了理论依据，为AD治疗提供了新的可能性。