从“能量障碍-炎症”交互影响的Akt/PGC-1α/NLRP3通路探讨地黄饮子治疗AD的补肾化痰作用

Recent studies have confirmed that “energy disturbance and inflammation” interaction via Akt/PGC-1α/NLRP3 pathway drived the course and deterioration of Alzheimer's disease (AD), and served as an important therapeutic targets for the AD. "Kidney-invigorating and Phlegm-eliminating" prescription named Dihuang Yinzi has been used in treatment in AD based on " Kidney-debility and Phlegm-stuck" pathogenesis, and the clinical effect is significant. Our previous study showed that Dihuang Yinzi could ameliorate energy impairment and inflammatory damage in AD mouse by modulating Akt and NF-κB. We speculate that "Dihuang Yinzi exerts anti-AD 'Kidney-invigorating and Phlegm-eliminating' effect by blocking the vicious cycle of inflammation/energy via Akt/PGC-1α/NLRP3 pathway". The current project will performed by focusing on intervention mechanisms of energy/inflammation and its effect on Akt/PGC-1α/NLRP3, with in vivo and in vitro experiments, by the way of the integrating neuroimaging and molecular biology techniques, from various angles of energy, inflammation, synaptic structure, apoptosis, cognition, etc. We will investigate integrated modulation of Dihuang Yinzi on the interaction of energy/inflammation at multiple levels of animal, tissues, cell, and molecular, to develop the theory of traditional Chinese medicine, and explore the breakthroughs of the treatment of AD.

近年研究证实，Akt/PGC-1α/NLRP3通路介导的“能量障碍-炎症”相互为恶的交互作用，是阿尔茨海默病（AD）病程启动与恶化的核心环节，为AD重要治疗靶标。“补肾化痰”方药地黄饮子基于AD“肾虚痰阻”病机进行治疗，效果显著。我们前期发现，地黄饮子通过调控Akt和NF-κB，改善AD小鼠脑能量障碍和炎症损伤。由此推论“地黄饮子由Akt/PGC-1α/NLRP3通路阻断能量障碍-炎症交互作用引发的恶性循环，发挥抗AD‘补肾化痰’功效”。本项目围绕地黄饮子对能量障碍-炎症交互作用的干预机理及其对Akt/PGC-1α/NLRP3调控机制的研究，结合体内外实验，整合神经影像和分子生物学技术，从能量、炎症、突触结构、细胞凋亡、认知等多个角度，在整体、组织、细胞分子等多水平上研究地黄饮子对能量障碍-炎症交互作用的整合调控机制，以新的视角阐释地黄饮子抗AD机理，丰富发展中医理论，探索AD治疗新突破。

本项目初步阐明了地黄饮子调节AD小鼠能量代谢-炎症交互作用的分子机制。体内实验显示，地黄饮子能够明显改善AD大、小鼠脑内能量代谢，保护线粒体结构与功能，明显抑制AD小鼠脑内炎症反应，显著抑制Akt/PGC-1α/NLRP3通路的激活。通过体外实验证实，Akt/PGC-1α/NLRP3通路是地黄饮子调节AD小鼠能量代谢-炎症交互作用的作用靶点。通过体内外实验，本研究初步揭示了地黄饮子抗AD益肾化痰功效的分子机制。进一步研究显示，地黄饮子还能够改善由能量障碍导致的内质网应激，地黄饮子君药肉苁蓉的活性成分松果菊苷的可以和小鼠及人类的PERK蛋白结合，为进一步厘定地黄饮子的作用靶标奠定了实验基础。本项目资助下共发表论文10篇，其中SCI论文2篇（影响因子分别为5.201和2.152），北大中文核心期刊7篇，科技核心期刊1篇。