中国药理学通报2024，Vol.40Issue(1)：90-98,9.DOI:10.12360/CPB202306007
基于PI3K/AKT/GSK-3β信号通路探讨EA改善APP/PS1双转基因小鼠认知功能障碍的内在机制
Mechanism of ellagic acid improving cognitive dysfunction in APP/PS double transgenic mice based on PI3K/AKT/GSK-3β signaling pathway
摘要
Abstract
Aim To investigate the effect of ellagic acid(EA)on cognitive function in APP/PS1 double-transgenic mice,and to explore the regulatory mecha-nism of ellagic acid on the level of oxidative stress in the hippocampus of double-transgenic mice based on the phosphatidylinositol 3-kinase/protein kinase B/gly-cogen synthase kinase-3(P13K/AKT/GSK-3β)signa-ling pathway.Methods Thirty-two SPF-grade 6-month-old APP/PS1 double transgenic mice were ran-domly divided into four groups,namely,APP/PS1 group,APP/PS1+EA group,APP/PS1+LY294002 group,APP/PS 1+EA+LY294002 group,with eight mice in each group,and eight SPF-grade C57BL/6J wild type mice(Wild type)were selected as the blank control group.The APP/PS1+EA group was given 50 mg·kg-1·d-1 of EA by gavage;the APP/PS1+LY294002 group was given 1.5 mg·kg-1·d-1 of PI3K inhibitor LY294002 by intraperitoneal injection;the APP/PS1+EA+LY294002 group was given 50 mg ·kg-1·d-1 of EA by gavage,and the APP/PS1+EA+LY294002 group was given 50 mg·kg-1·d-1 of EA by gavage.The WT group and APP/PS1 group were given equal volume of 10％dimethyl sulfoxide(DMSO)by gavage at the same time.Morris water maze was administered once a day for 60 days,and the learning and memory abilities of mice were measured by immunohistochemistry and protein immunoblotting(WB),and the expressions of PI3 K,AKT and GSK-3β-related proteins were detected by transmission elec-tron microscopy.Results Compared with the WT group,the other four groups all showed an increase in escape latency(P＜0.05)and a significant decrease in the number of plateaus crossed(P＜0.01);PI3K and AKT protein expression was significantly lower in the APP/PS1 group,APP/PS1+LY294002 group and APP/PS1+EA+LY294002 group(P＜0.01),GSK-3β expression was significantly higher(P＜0.01);PI3 K expression was lower(P＜0.05),AKT expres-sion was significantly lower(P＜0.01)and GSK-3βexpression was higher(P＜0.05)in the APP/PS1+EA group;compared with the WT group,the APP/PS1 group had a lower number of hippocampal neuronal cells,disrupted mitochondrial structure,and most mito-chondria appeared swollen.The number of neuronal cells in the APP/PS1+EA group was higher than that in the APP/PS1 group,and the mitochondrial structure was clearer,with clear mitochondrial cristae and mild mitochondrial edema.Microtubules and microfilaments were arranged more neatly and orderly.Conclusions Ellagic acid improves learning and memory abilities,re-duces hippocampal neuronal cell damage and apoptosis in AD model mice,and its mechanism of action may in-volvereducing hippocampal oxidative stress levels in AD model mice by regulating PI3K,AKT,GSK-3β and other related proteins.关键词
APP/PS1双转基因小鼠/阿尔茨海默病/鞣花酸/磷脂酰肌醇3-激酶/蛋白激酶B/糖原合成酶激酶-3Key words
APP/PS1 double transgenic mice/Alzhei-mer's disease/ellagic acid/phosphatidylinositol 3-ki-nase(PI3K)/protein kinase B(AKT)/glycogen syn-thase kinase-3(GSK-3β)分类
医药卫生引用本文复制引用
仲丽丽,刘宏,路鑫,于颖,赵秦妍,张静,刘彤慧,倪雪妍,车艳玲,吴丹..基于PI3K/AKT/GSK-3β信号通路探讨EA改善APP/PS1双转基因小鼠认知功能障碍的内在机制[J].中国药理学通报,2024,40(1):90-98,9.基金项目
国家自然科学基金青年项目(No 81403288) （No 81403288）
国家自然科学基金面上项目(No 82074288) （No 82074288）
黑龙江省自然科学基金联合引导项目(No LH2022H068) （No LH2022H068）
中国博士后科学基金资助课题(No 2015M581496) （No 2015M581496）
黑龙江中医药大学研究生创新科研项目立项基金(No 2022yjscx012,2019yjscx011) （No 2022yjscx012,2019yjscx011）
黑龙江省卫生健康委科研课题立项(No 20220202080996) （No 20220202080996）
