老年性痴呆（AD）具有难以逆转的发病特征，目前仍无有效治疗药物，必须采取"窗口前移"的研究策略，依据中医"治未病"思想及有效方剂，寻找AD前临床期（preclinical AD）的防治药物。本课题在生脉散防治AD药效和成分研究基础上，采用整合代谢组学和血清药物化学的一体化研究方法，通过Aβ诱导AD大鼠模型体液中整体代谢物的动态分析，鉴定AD发生早期的代谢标记物，追溯相关代谢经路，评价生脉散对AD代谢标记物变化的干预作用阐释其整体作用机制；进而通过基于Aβ诱导AD大鼠模型的生脉散体内成分ADME类药性研究，筛选生脉散体内markers，经分子对接预测活性，确定生脉散体内直接作用物质；分析代表性体内直接作用物质与生脉散整体调节代谢标记物变化的相关性，阐明生脉散药效物质基础和多成分、多靶点协同作用机制，并形成生脉散早期防治AD的有效成分组合。本课题对于实施AD早期诊断、早期干预具有重要科学意义。

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder. It must take the forward strategy of therapeutic window, looking pre-clinical stage drugs for prevention and treatment of Alzheimer's disease (AD). According to disease prevention theory of traditional Chinese medicine (TCM), and formula may act synergistically through its multiple components, and provide a effective method to prevent AD. Based on our research of efficacy and in vivo constituents f Shengmai San, the dynamic changes of endogenic metabolites in biofluids of AD model rats induced by Aβ is analyzed by the UPLC-HD/MS based metabonomics to identify the metabolic biomarkers which exist in early stage of AD and evaluate the intervention effects of Shengmai San which is effective to prevent AD. Furthermore, the pharmacokinetics on the absorption distribution, metabolic and excretion is monitored to screen the marker components of Shengmai San for preventing AD. Molecular docking is applied to forecast their activities. Finally, the few typical bioactive components in vivo are selected to evaluate their effects on the metabolic markers of AD. Therapeutic basis and the action mechanism of Shengmai San is clarified, and a new drug combination consisting of several effective components of Shengmai San is abtained. The project has important scientific significance in studying the early stage diagnose and early intervention of AD, and screening the effective components preventing AD of TCM formula.

老年痴呆症（AD）是一种不可逆的慢性神经系统退行性疾病，目前尚无有效治疗药物；将研究窗口前移，发现其早期发生的生物标记物，实施早期准确诊断和早期干预，是延迟或阻断AD发展的有效方案。鉴于经典脑内注射Aβ蛋白诱导老年痴呆大鼠模型不能反映AD早期发生的过程，本课题选择三氯化铝联合D-半乳糖诱导老年痴呆大鼠模型和APP/PS1转基因老年痴呆小鼠模型，观察AD的发生发展过程，评价生脉散的干预作用，而利用Aβ诱导细胞模型评价效应关联成分的作用。首先，结合行为学等经典AD评价方法，利用代谢组学技术分析了三氯化铝联合D-半乳糖诱导老年痴呆大鼠模型发生发展过程代谢轮廓及代谢标记物的变化，发现机体色氨酸代谢异常，直至大鼠出现明显认知障碍时伴随出现脂质代谢异常。生脉散通过其体内成分五味子醇甲、五味子醇乙、戈米辛D和7,8-二羟基-3-去甲基五味子醇甲和人参皂苷RK3调控色氨酸代谢和脂质代谢，为生脉散防治老年痴呆的潜在药效物质基础。对五味子醇甲进行干预AD大鼠模型的作用评价，进一步明确了五味子醇甲是生脉散预防老年痴呆的主要药效物质基础。然后，利用代谢组学技术鉴定APP/PS1双转基因老年痴呆症小鼠模型发生各阶段代谢标记物，发现与AD相关的6条代谢经路，包括氨基酸代谢、核苷酸代谢、辅酶因子及维生素代谢、脂类代谢、能量代谢和碳水化合物代谢。生脉散主要调节氨基酸代谢、核苷酸代谢和辅酶因子及维生素代谢，同时追溯到生脉散调节的关键酶包括犬尿氨酸转氨酶、黄嘌呤脱氢/氧化酶和醛氧化酶。同时利用血清药物化学方法，分析鉴定了生脉散干预APP/PS1转基因小鼠的体内直接作用物质，为生脉散预防AD的潜在药效物质基础。进一步选择生脉散体内高表达成分五味子醇甲，利用Aβ诱导PC12细胞模型确认了其抗老年痴呆作用。本项目为实施AD早期诊断和早期干预及生脉散防治AD创新药物开发奠定了基础。本项目共发表论文18篇，其中SCI收录期刊论文13篇；登记计算机软件著作权1项；培养博士研究生3名，硕士研究生3名。