基于“痰浊瘀血”理论从蛋白质异戊二烯化修饰探讨当归芍药散改善AD认知功能的机制

Metabolic syndrome (MS) is an important risk factor for the onset of Alzheimer's disease (AD), and traditional Chinese medicine for the prevention and treatment of MS can improve AD cognitive dysfunction, but its exact mechanism has not been elucidated. Lots of researches showed that both the MS and AD, which are closely related with "phlegm congestion turbid evil" in Chinese medicine, exist correlation with protein prenylation translational modifications (PPTM). Our previous studies confirmed that regulating protein PPTM levels could enhance synaptic plasticity and improve the cognitive function in AD animal model. We speculate that the abnormal PPTM protein is the main reason for glucose and lipid metabolism disorder in AD brain and related nerve damage on the cognitive loop, and the traditional Chinese Medical prescription based on the method of “conditioning liver and spleen” can regulate protein level of PPTM to improve the cognitive function of AD. In this study, we investigate the connection between PPTM protein and cognitive dysfunction induced by glucose and lipid metabolism disorder combined with Abeta, and intervene by the traditional Chinese Medical prescription based on the method of "conditioning liver and spleen and improving phlegm and blood stasis", and identify the PPTM protein of synaptic plasticity in MS combined with Abeta through biochemical/proteomic methods combination bioinformatics analysis. We attempt to illuminate the mechanism by which the synaptic dysfunction induced by MS combined with Abeta is related to its potential ability in PPTM. This study will enrich the scientific connotation of the pathogenesis of "cognitive dysfunction by phlegm and blood stasis" in AD and lead to the discovery of other novel therapeutic targets for AD.

代谢综合征（MS）是阿尔茨海默病（AD）发病的重要危险因素，防治MS的中药能改善AD的认知功能，但其确切机制尚未阐明。鉴于“痰浊瘀血”在AD和MS发病中起着关键作用，且有研究表明，MS和AD发病均与蛋白异戊二烯化修饰（PPTM）异常存在联系。我们前期结果显示，调控蛋白PPTM水平能增强突触可塑性和改善AD动物的认知功能，我们推测蛋白PPTM异常是AD脑糖脂代谢紊乱的主要原因并损害认知相关神经环路，从肝脾论治的中药复方能通过该机制改善AD认知功能。本项目从整体动物和体外细胞模型研究糖脂代谢障碍结合Aβ干预诱导的神经损害和认知功能下降以及对蛋白PPTM的影响，探讨两者间的相关性及联系机制，并以肝脾同调痰瘀并治的中药复方干预，结合生物信息学手段筛选和分析影响突触可塑性的PPTM蛋白，探索突触损伤的蛋白质翻译后调控机制，丰富AD“肝脾失调，痰瘀蒙窍”病机的科学内涵，为防治AD寻找新的靶点和药物。

阿尔茨海默病（AD）是最常见的老年期痴呆，目前尚缺乏有效的治疗措施。大量的研究证据表明代谢综合征（MS）是阿尔茨海默病（AD）发病的重要危险因素，且防治MS的中药能改善AD的认知功能，但其确切机制尚未阐明。鉴于“痰浊瘀血”在AD和MS发病中起着关键作用，且有研究表明，MS和AD发病均与蛋白异戊二烯化修饰（PPTM）异常存在联系。我们推测蛋白蛋白异戊二烯化修饰水平异常是AD脑糖脂代谢紊乱的主要原因并损害认知相关神经环路，从肝脾论治的中药复方当归芍药散能通过该机制改善AD认知功能。首先，我们通过研究胰岛素抵抗结合Aβ对脑内神经元蛋白异戊二烯化⽔平的影响及与突触损伤的相关性及联系机制。然后，运用经典的分⼦⽣物学⼿段探讨当归芍药散改善神经突触可塑性与蛋白 PPTM 之间的联系机制。最后，通过系统生物学、转录组学及蛋白组学筛选当归芍药散改善认知功能的具体靶点。我的研究结果证实：①在胰岛素抵抗状态下，Aß能提高FNTB，HMGR和GGT-1的水平，损伤突触结构和降低突触相关蛋白水平，蛋白异戊二烯化水平（特别是法尼基修饰水平）升高明显，同时伴有神经炎症水平升高，具体机制与mTOR/AMPK能量代谢通路异常有关。②当归芍药散能降低Aβ诱导的神经元蛋白异戊二烯化修饰水平，改善Aß诱导的神经细胞突触相关蛋白水平，具体机制可能通过影响转录因子p-SREBP活化水平影响mTOR/AMPK能量代谢通路有关。③当归芍药散能通过影响神经元迁移和突触传递相关的LncRNAs改善认知功能，而这些与异戊二烯化修饰蛋白的功能密切相关。本项目基本证实了当归芍药散通过影响mTOR/AMPK能量代谢通路调节神经元蛋白异戊二烯化修饰水平，修复损伤突触，发挥抗痴呆效用；同时从蛋白质异戊二烯化翻译后修饰调控机制丰富了 AD“肝脾失调，痰瘀蒙窍”病机的科学内涵，为防治 AD 寻找新的靶点和药物。