Effects And Its Underlying Mechanisms Of Icariside Ⅱ On Spatial Learning And Memory Impairment In Alzheimer’s Disease Model Mice

Objective: The present study was designed to observe the neuroprotective effects of icariside II(ICS Ⅱ)on learning and memory impairment in APP/PS1 transgenic mice,and further explore its possible mechanisms.Methods: Nine-month-old male APP/PS1 transgenic mice and age-matched male wild type(WT)mice were randomized divided to six groups: APP/PS1 control group(n=12),APP/PS1+ICS Ⅱ low-dose group(n=12),APP/PS1+ICS Ⅱ high-dose group(n=13),WT control group(n=10),WT+ICS Ⅱ low-dose group(n=10),WT+ICS Ⅱ high-dose group(n=10).APP/PS1 and WT treated groups were orally administered with ICS Ⅱ(10,30mg/kg/d)and control groups were received volume-matched normal saline for three months.Morris water maze was used to examine the learning and memory function of mice,and then mice were sacrificed.Senile plaques in the hippocampus of APP/PS1 transgenic mice were observed by thioflavine S staining.Nissl staining was used to evaluate the survival neurons in the hippocampus of mice.The levels of Aβ1-42/Aβ1-40 and s APPα/s APPβ,the protein expression of APP,ADAM10,PDE5 A,the protein level of BACE1 and its related signaling pathways PPARγ protein expression and e IF2α/PERK phosphorylation levels in the hippocampus and cortex of mice were detected by Western blot,respectively.Results: Compared with the WT control group,the mean escape latency was apparently increased and the percentage on time spent in target quadrant was dramatically decreased in APP/PS1 transgenic mice.Moreover,senile plaques in the hippocampus of APP/PS1 transgenic mice appears positive staining;the amount of neuronal cells were decreased;the protein expression of APP,PDE5 A and the levels of Aβ1-42/Aβ1-40 were increased;the levels of ADAM10,s APPα and PPARγ were decreased,BACE1 expression,s APPβ level and e IF2α/PERK phosphorylation levels were enhanced.However,compared with APP/PS1 control group,the mean escape latency of mice were shorter than those in APP/PS1+ICS Ⅱ treated groups,and the percentage on time spent in target quadrant were dramatically increased;the number of neuronal cells were increased;the formation of senile plaques was fewer;the protein expression of APP,PDE5 A and the levels of Aβ1-42/Aβ1-40 were decreased;the expression of ADAM10,s APPα and PPARγ were increased;BACE1expression,s APPβ level and e IF2α/PERK phosphorylation levels were less than those in APP/PS1+ICS Ⅱ groups.Conclusion: Under the experimental conditions,ICS Ⅱ effectively attenuates spatial learning and memory impairment,neuronal loss and the formation of senile plaques in APP/PS1 transgenic mice,and its underlying mechanism may,at least partly,be related to the inhibition of Aβ production and the reduction of PDE 5 content.