阿尔茨海默病是影响人类健康的主要疾病之一。但该疾病治疗药物少、疗效不佳，当前研发单一靶点抗AD新药屡屡受挫，亟待新的防治策略。天然产物（NPs）、特别是特殊三维结构的NPs是活性先导物的重要源泉。申请人长期从事藤黄科植物化学成分研究。在前期基础中，从该科植物发现大量新的多环NPs（如PPAPs）；部分PPAPs具AChE酶抑制活性；非含氮金刚烷等PPAPs可调节PP2A活性降低Tau蛋白磷酸化水平，还可调节BACE1活性减少APPβ和毒性Aβ的产生发挥多重抗AD作用。本课题拟运用1H NMR联合HPLC-DAD表征NPs的策略高效地开展藤黄科植物NPs研究；基于BACE1和PP2A等蛋白激酶抑制剂筛选模型探讨该科植物多环NPs抗AD活性及其构效关系，以活性显著NPs为分子探针、探讨其作用机制和靶蛋白，以期从中发现新型多靶点抗AD天然先导化合物，为藤黄科物种资源的综合开发利用提供科学依据。

Based on the World Alzheimer Report 2016, more than 47 million people currently live with dementia worldwide, and the total estimated cost of dementia will rise to as much as US$ trillion by 2018, it is thus undoubtedly true that AD is a major threat to the health of the global populations. Given the sophisticated pathological mechanisms in AD, the limited available drugs, as well as the challenges of searching individual molecular targets for drugs that can modify the course of AD, new anti-AD drugs and treatment approaches are urgently needed. Natural products (NPs) and their molecular frameworks, especially those compounds that contain polycyclic hydrocarbon scaffolds, have a long tradition as valuable starting points for medicinal chemistry and drug discovery. To meet the urgent need to develop new agents for AD, a practicable strategy is to delve into bioactive NPs or lead compounds from plant-derived secondary metabolites. . This decade, many endeavors of our group had been devoted to NPs with polycyclic motifs from the medicinal plants (such as the family Clusiaceae) and their biological functions, which led to the discovery of a series of structurally novel and bioactive polycyclic NPs. Our previous investigations on traditional Chinese medicinal herbs have established good basis for the research proposal. Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a family of naturally occurring polycyclic NPs that characterized as the main secondary metabolites of the plants in Clusiaceae family, especially the genus Hypericum. PPAPs are also one of the hot research topics in natural products chemistry field because the promising pharmacological effects and challenging polycyclic scaffolds. During our latest work, we had isolated and identified scores of new PPAPs derivatives from the plants including H. perforatum (also known as St John’s Wort), collected from Shennongjia Districts, Huazhong area of China, which enriched our knowledge of chemical constituents of plants from the Clusiaceae family. . Before this application, the anti-AD bioassays of the selected NPs in vitro were performed, the primary results showed that: 1) some of PPAPs exhibited potent acetylcholinesterase inhibitory activities (IC(50) value of 3.98 μM); 2) non-nitrogen-containing homo-adamantane type PPAPs and some novel tricyclic acylphloroglucinols with bicyclo[3.3.1] ring system seemed to have anti-AD potential with multiple target sites of action, they could not only the regulate phosphorylation level of Tau protein through the activation of PP2A, but also attenuate the generation of APPβ and Aβ by modulating BACE1 activity. The proposed project are expected to 1) implement a combinatory strategy of proton NMR and HPLC-DAD effectively to find more polycyclic NPs from the species of the family Clusiaceae; 2) perform multi-targeted natural products evaluation based on screening of their biological activities upon AD related protein kinases, such as PP2A and BACE1 kinases, and their structure-activity relationships (SAR) analysis; 3) investigate mode of action (MOA) of polycyclic NPs from Clusiaceae plants with significant anti-AD activity both in vitro and in vivo. The results of this project will not only provide novel lead compounds function as multi-target directed ligands for Alzheimer’s disease, but also offer scientific basis for the comprehensive development and utilization of these medicinal important plants in Clusiaceae family.