阿尔茨海默病(AD)严重危害人类健康，发病机理十分复杂，脑内β-淀粉样蛋白(Aβ)沉积激活小胶质细胞引起的神经炎症是AD的核心病理机制之一，寻找抑制神经炎症天然先导化合物是研发防治AD新药的重要策略。我们前期研究发现短柄枹栎种子中总三萜具有显著的抗神经炎症及神经保护活性，同时能有效改善AD小鼠空间学习记忆能力，减少大脑皮层和海马区域Aβ沉积及明显抑制脑内神经炎症。本项目拟对短柄枹栎中三萜类进行分离鉴定，通过LC-MS/MS(MRM)建立三萜类化合物的特征轮廓谱，追踪分离三萜成分，利用抗神经炎症及神经细胞保护活性模型筛选出活性化合物。利用生物信息学网络模型及分子药理学手段预测和验证活性化合物抗AD的作用机制，筛选出抗AD作用机制明确的先导化合物。采用Pipeline Pilot软件探讨先导化合物的成药性，对成药性良好的先导化合物进行转基因AD小鼠体内活性及作用机制研究，优选出抗AD候选药物。

Alzheimer's disease (AD) serious harm to human health and its pathogenesis is very complex. The neuroinflammation caused by activated microglia, which is activated by amyloid β (Aβ) pledges, is one of the core mechanisms. Searching for the neuroinflammatory inhibitors from natural resources is an important strategy for R&D of the new anti-AD drug... Our previous study found that the total triterpenoids in the seeds of Quercus serrata var. brevipetiolata exhibited obvious anti-neuroinflammatory and neuroprotective activity, and could significantly improve the spatial learning and memory ability of AD transgenic mice, reduce the Aβ deposition in the areas of mouse cerebral cortex and hippocampus, and inhibit neuroinflammation in the brain. .. This project will be focused on isolation and purification of the triterpenoids with anti-AD activity from the seeds of Quercus serrata var. brevipetiolata by a variety of chemical and chromatographic methods. The chemical structure of triterpenoids will be identified through the integrated spectroscopic and chemical methods. LC-MS/MS (MRM) will be applied to establish the characteristic profile of the triterpenoids to track and isolate the triterpenoids. Anti-neuroinflammation bioactivity and mechanism of the isolated triterpenoids would be predicted by the network models of systems biology, and then verified by molecular pharmacological methods to screen out the lead compounds which have clear anti-AD mechanism. .. Subsequently, preliminary experiments in pharmacokinetics (ADME/T) of the lead compounds were also carried out to the candidates with potent anti-AD activity through Pipeline Pilot software. For the candidates with good druggability and prospects, the in vivo anti-AD activity would be conducted in APP/PS1 transgenic AD mice to clarify their anti-AD mechanisms. Thus, these data may consider together to screen out anti-AD candidate in the new drug development.