Neuroprotective Effect Of Icariin On APP/PS1/Tau Triple Transgenic Alzheimer’s Disease Mice By Improving Cerebral Glucose Metabolism Dysfunction

Objective:To investigate the effect of icariin（ICA）on learning and memory function in APP/PS1/Tau triple transgenic Alzheimer’s disease（3×Tg-AD）mice,and further explore its possible mechanisms.Methods:Three-month-old male 3×Tg-AD mice were randomly divided into three groups（n=10 per group）:3×Tg-AD group,3×Tg-AD+ICA 30 mg/kg group,3×Tg+ICA60 mg/kg group;sex-and age-matched wild type（WT）mice were randomly divided into two groups（n=10 per group）:WT group,WT+ICA 60 mg/kg group.3×Tg-AD and WT treated groups were orally administered with ICA once a day for 5 months,and control groups were given an equal volume vehicle（0.5%Tween-80 in distilled water）.Morris water maze was used to detect the learning and memory function of mice;rotarod test,open-field test and nest-construction test were applied to evaluate motor function and instinctive behavior.Cerebral glucose metabolism in 3×Tg-AD mice was observed by¹⁸F-FDG microPET imaging technique.Nissl staining,HE staining and immunofluorescence were used to evaluate the survival neurons and Aβdeposition in hippocampus of mice.Glucose oxidase assay was used to detect glucose contents in cortex and hippocampus of mice.Hexokinase（HK）,phosphofructokinase（PFK）and pyruvate Kinase（PK）assay kit were used to detect their activities in cortex and hippocampus of mice.The levels of APP,Aβ_1-40,Aβ_1-42 and the phosphorylation level of Tau protein at PHF-1（Ser396/404）,Ser199/202,Thr231,Thr217,Ser422 sites,the protein expression of glucose transporter 1（GLUT1）,GLUT2,GLUT3,HK1,PFK1,PKM1（subtypes of HK,PFK and PK respectively）and pyruvate dehydrogenase E1component subunit alpha（PDHA1）in hippocampus of mice were detected by Western Blot.Results:Behavioral examination revealed a profound decrease in learning and memory function,motor function and nest-construction ability,accompanied by a decrease in number of neuronal cells and Aβaggregation in 3×Tg-AD mice.Moreover,the per gram cerebral tissue 18F-FDG uptake rate was reduced and the glucose contents in the cortex and hippocampus were increased in 3×Tg-AD mice.In addition,Western blot analysis showed that the expression of APP,Aβ_1-40,Aβ_1-42 proteins and the levels of Tau protein phosphorylation at PHF-1,Ser199/202,Thr231,Thr217 and Ser422 sites were significantly increased,followed by a decrease in expression of GLUT1,GLUT2,GLUT3 and reduction of HK1,PFK1,PKM1 and PDHA1 activities in hippocampus of3×Tg-AD mice.After ICA treatment,the learning and memory function,motor function and nest-construction ability of mice were increased;the number of neurons were increased,Aβdeposition were decreased;18F-FDG uptake rate in brain tissue were increased,glucose concentration in hippocampus and cortex were decreased;the content of APP,Aβ_1-40,Aβ_1-42 in hippocampus were decreased,the phosphorylation level of Tau related sites were decreased;protein expression of GLUT1,GLUT2,GLUT3 were up-regulated and the activities of HK1,PFK1,PKM1 and PDHA1 were increased.Conclusion:Under the experimental conditions,ICA has a neuroprotective effect on3×Tg-AD mice,and its mechanism is related to the increase of glucose transports and the promotion of glucose decomposition to improve cerebral glucose metabolism dysfunction.