基于“化痰开窍-自噬机制关联”新假说探讨“远志-石菖蒲”药对干预AD的分子机制

Alzheimer's disease (AD) has become a growing public health crisis. There is no effective interventions for AD due to its complex pathogenesis. Traditional Chinese medicine (TCM) has grate potential for AD prevention owe to its multi-channel, multi-link, multi-target and integrated disease intervention advantages. According to TCM，TanZhuo ZuQiao is critical for the development of AD. The couplet medicine, “Radix Polygalae & Acorus tatarinowii Schott”(YZ-SCP), is a classic representative Chinese herbal medicine for HuaTan KaiQiao. Our previous studies have showed that YZ-SCP is effective in therapeutic intervention of AD major pathological products. However, the molecular mechanism remains to be elucidated. Because of the similar pathophysiological mechanisms between TanZhuo ZuQiao and mulfuction of autophagy in the pathogenesis of AD, we have proposed a new hypothesis that HuaTan KaiQiao is correlated with autophagy induction. Based on this hypothesis and our previous studies, we are planning to investigate the effect of YZ-SCP on cognitive function and neuronal protection in AD models. We also want to investigate the regulation of autophagy-lysosome pathway by YZ-SCP, and elucidate molecular mechanisms of autophagy-mediated clearance of AD major pathological products. Our study will provide scientific basis for the clinical intervention of AD and blazed new trails for this field by Traditional Chinese Medicine.

阿尔茨海默病(AD)已成为影响人类健康的重大疾患，AD病因复杂，目前对其持续恶化的病理进程仍缺少有效干预手段。中医药以其多途径、多环节、多靶点综合干预的优势在AD防治领域潜能巨大。中医认为痰浊阻窍是AD的重要病机，我们研究发现化痰开窍经典药对“远志-石菖蒲”对AD核心病理产物的干预效果显著，但其分子机制尚有待揭示。基于AD脑内痰浊阻窍与自噬障碍导致病理产物集聚损伤神经元及其高级认知功能的病理生理机制类同，我们提出了“化痰开窍-自噬机制关联”新假说。本项目拟基于该假说，在本团队20多年中医药防治AD系列研究成果基础上，系统研究“远志-石菖蒲”对AD模型认知功能、特征性神经病理产物及神经元保护的影响，探讨其对细胞自噬的调控作用，阐明其干预 AD 核心病理产物、保护神经元的关键分子机制，为其临床干预 AD及“化痰开窍-自噬机制关联”新假说提供科学实验依据，并为本病中医药防治开辟新思路。

阿尔茨海默病(AD)已成为影响人类健康的重大疾患，AD病因复杂，目前对其持续恶化的病理进程仍缺少有效干预手段。中医药以其多途径、多环节、多靶点综合干预的优势在AD防治领域潜能巨大。中医认为痰浊阻窍是AD的重要病机，我们研究发现化痰开窍经典药对“远志-石菖蒲”对AD核心病理产物的干预效果显著，但其分子机制尚有待揭示。基于AD脑内痰浊阻窍与自噬障碍导致病理产物集聚损伤神经元及其高级认知功能的病理生理机制类同，我们提出了“化痰开窍-自噬机制关联”新假说。. 本项目严格按照原申请计划完成相关的科研实验，达到预期研究目标，明确了“远志-石菖蒲”具有显著改善AD模型动物行为学和神经病理学的作用，并证实了“远志-石菖蒲”对AD细胞和动物病理模型自噬溶酶体途径蛋白降解活性的影响。进一步的分子药效机制研究发现，远志-石菖蒲药对中所含的远志皂苷B在诱导神经细胞自噬中发挥了重要作用。远志皂苷B能显著降低mTOR蛋白及其下游底物的磷酸化水平，抑制mTOR通路活性激活细胞自噬。定量蛋白质组学-iTRAQ 研究还发现远志-石菖蒲药对对神经细胞自噬的调控是通过多靶点协同发挥作用，远志-石菖蒲药对显著上调了自噬促进因子AMPK、Bcl-XL、ATG3、Rab33B的表达，下调了自噬抑制因子Rubicon的表达。本研究基本阐明了“远志-石菖蒲”药对干预AD核心病理产物的分子机理，为其临床应用提供分子神经药效学支撑，并为“化痰开窍-自噬机制关联”新假说提供了科学实验依据。.