多途径干预复杂性疾病AD的发生和发展为治疗AD的新的有效策略，DYRK1A在诱发AD的多个重要途径中起着核心作用，为抗AD的新靶点。本课题组前期研究表明苦木总生物碱(TAPQ)具有抗AD作用，可能的作用机制为：β-咔巴啉生物碱的体内代谢物质（原型或代谢产物）通过抑制DYRK1A活性及其下游AD相关信号通路，减少NFTs和Aβ生成，从而改善AD。因此，本项目拟在TAPQ化学成分和指纹图谱研究的基础上解析体内代谢物质，再以“体内—脑内”分析关联、分离/合成和DYRK1A抑制活性测试相结合的方法确认并获得靶器官—脑内药效物质；用多个细胞模型研究脑内药效物质对DYRK1A介导的tau蛋白磷酸化和Aβ生成的影响。以这种“有效部位化学成分研究—体内代谢物质解析—脑内药效物质确证—作用机制研究”层间递进的研究模式，系统阐明TAPQ抗AD的体内效应物质及作用机制。

Multi-pathway intervention of the onset and development of Alzheimer’s disease (AD) is considered as a novel and effective strategy for the treatment of this serious disease. The overactivation of DYRK1A plays important roles on the activation of many pathogenic pathways including the formations of NFTs and Aβ, which makes it be a new target for treating AD. Previous work in our lab suggest that the total alkaloide from Picrasma quassioides (TAPQ) has the capability to treat AD, the possible mechanisims are that β-carboline alkaloides or their metabolites can reduce the formations of NFTs and Aβ through suppressing the activities of DYRK1A and its downstream AD-related signal pathways, and thereby alleviating some symptoms of AD. In this project, we plan to test our hypothesis using a new research pattern called “Chemical constituents analysis - In vivo metabolites identification - Bioactive compounds screening- In-vitro mechanism deciphering”. The components in feces, urine and bile after oral administration of TAPQ will be analyzed by LC-Q-TOF-MS/MS and LC-DAD-MS/MS combine with chemical compositions and chemical fingerprinting of TAPQ to clarify its metabolites in vivo. Then, the metabolites will be further screened by pharmacokinetic in rat brain and DYRK1A kinase assay in vitro to comfire the internal active components. Finally, the influence of bioactive metabolites to DYRK1A-induced tau protein phosphorylation and the formation of Aβ can be tested by using several cell lines. Thus, systematically investigate and decipher the internal active components and action mechanisms of TAPQ for AD.