基于β淀粉样蛋白探讨苯乙醇苷类化合物抗阿尔茨海默症的作用机制  

Exploring mechanism of phenylethanoid glycosides against Alzheimer’s disease based on amyloid β-protein

作　　者：陈胜玮 许峥 王天麟[2] 陈俊杰[3] CHEN Shengwei;XU Zheng;WANG Tianlin;CHEN Junjie(Nantong Haimen People's Hospital,Nantong 226100,Jiangsu,China;Nanjing University of Chinese Medicine,Nanjing 210023,Jiangsu,China;Affiliated Hospital of Nantong University,Nantong 226000,Jiangsu,China)

机构地区：[1]南通市海门区人民医院,江苏南通226100 [2]南京中医药大学,江苏南京210023 [3]南通大学附属医院,江苏南通226000

出　　处：《上海中医药大学学报》2023年第1期62-69,共8页Academic Journal of Shanghai University of Traditional Chinese Medicine

基　　金：江苏省高校自然科学研究面上项目(13KJB350005);南通市卫生健康委员会科研项目(QA2021001)。

摘　　要：目的:基于β淀粉样蛋白(Aβ)探讨苯乙醇苷类化合物抗阿尔茨海默症(AD)的作用机制。方法:以天然产物库为筛选对象,运用软件Autodock以对接方法从库中筛选出与β分泌酶1(BACE1)对接较好的化合物,以对接打分作为挑选标准,挑选出候选化合物,并测试这些化合物在10μmol/L时与BACE1的亲和力,分析候选化合物的结构特征,最终挑选1~2个化合物作为靶标分子,采用Western blot法检测与Aβ相关的蛋白表达水平。结果:按照对接打分由高至低排序筛选出8个天然产物,其中3个化合物在10μmol/L时与BACE1的结合力超过了60%;结构分析发现有2个化合物的结构均属于苯乙醇苷,最终挑选大车前苷和连翘酯苷作为靶标化合物;大车前苷和连翘酯苷对BACE1的IC_(50)分别为(3.86±0.21)μmol/L和(4.52±0.29)μmol/L;大车前苷和连翘酯苷能显著下调大鼠神经元细胞中的BACE1、sAPPβ的表达水平(P<0.05,P<0.01,P<0.001),上调α-分泌酶(ADAM10)的表达(P<0.05,P<0.01)。结论:苯乙醇苷类化合物大车前苷和连翘酯苷能通过下调BACE1、sAPPβ,上调ADAM10的表达来抑制Aβ的表达,从而减缓AD的发展进程,这为基于Aβ通路抗AD的研究提供了优质的先导化合物。Objective: To explore the mechanism of phenylethanoid glycosides against Alzheimer’s disease(AD) based on amyloid β-protein(Aβ). Methods: Taking the natural product library as the screening object, the Autodock software was used to screen out compounds that were well docked with β-secretase 1(BACE1) from the library by docking method. Grid Score was used as the selection standard to select candidate compounds. The affinity of these compounds with BACE1 at the concentration of 10 μmol/L was tested, and their structural characteristics were analyzed, and 1~2 compounds were finally selected as target molecules. Western blot was conducted to detect the expression levels of Aβ related proteins. Results: Eight natural products were screened out according to Grid score from high to low. Among them, the binding affinity of 3 compounds with BACE1 was more than 60% at 10 μmol/L. The structural analysis showed that 2compounds belonged to phenylethanoid glycoside. Plantamajoside and forsythiaside were finally selected as the target compounds. The IC_(50)of plantamajoside and forsythiaside against BACE1 were(3.86±0.21) μmol/L and(4.52±0.29) μmol/L, respectively. The expression levels of BACE1 and sAPPβ in rat neurons were significantly down-regulated by plantamajoside and forsythiaside(P<0.05, P<0.01, P<0.001), while the expression of α-secretase(ADAM10) was significantly up-regulated(P<0.05, P<0.01). Conclusion: The phenylethanoid glycosides plantamajoside and forsythiaside can inhibit the expression of Aβ by down-regulating the expressions of BACE1 and sAPPβ and up-regulating the expression of ADAM10, which slows down the development of AD. And this provides the high quality of lead compounds for the research of Aβ pathway against AD.

关 键 词：阿尔茨海默症 大车前苷 连翘酯苷 Β淀粉样蛋白 BACE1 

分 类 号：R285[医药卫生—中药学]