Changes Of Volume Of Entorhinal Cortex And Hippocampus In APP/PS1 Mice At Different Stages And Their Effects On Learning And Memory Ability

Objective:In this study,the aim was to observe the changes of gray matter(entorhinal cortex and hippocampus),amyloid P-protein(AP)deposition,and test learning and memory ability-combined behavior test as well,then further analysis their(volume and Aβ deposition)relationship with learning and memory ability in APP/PS1 transgenic mouse model of Alzheimer’s disease and finally to identify whether the volume of gray matter and Aβdeposition can be used as a reference index for the severity of cognitive dysfunction.Methods:Male APP/PS1 double transgenic mice aged 2,6,12 months and the same aged wild type mice were divided into two groups respectively(12 mice in every groups)based on age.The mice brains were scanned with T2WI with 7T small animal MRI,then analysis changes of gray matter volume in mice at each time point.New object recognition test and Morris water maze was used to estimate the abilities of learning and memory.The deposition of Aβ in the hippocampus and entorhinal cortex were tested by Thioflavin-s.Based on the above results,to analysis the correlation between gray matter volume,Aβ deposition and learning and memory.Results:(1)Learning and memory function:New object recognition test:There was no sign-ificant difference in the recognition index of the same object between the two groups.(P>0.05);Compared with the WT group mice,the recognition index of the new object was significantly decreased in the APP/PS1 group at the age of 6 and 12 months.(P<0.05);However,there was no significant difference in the recognition index between the two groups at the age of two months.(P>0.05).Morris water maze task:Compared with WT group,the latency to the hidden platform increased significantly and the times of passing through the position where the platform had removed markedly decreased(P<0.01)in the APP/PS1 group aged 6 and 12 months.(P<0.01);However,there was no significant difference in the escape latency and the number of crossing the platform between the two groups at the age of 2 months.(尸>0.05)(2)The volume of grey matter in region of interest:Compared with the WT group,the volume of grey matter in entorhinal cortex and hippocampus was significantly decreased in the APP/PS1 group at the age of 12 months(P<0.001).The volume of olfactory cortex decreased significantly in 6-month-old APP/PS1 mice(P<0.01),but there was no significant difference in hippocampal volume(P>0.05).However,there was no significant difference between the two groups at the age of 2 months(P>0.05);The entorhinal cortex and hippocampus of mice showed age-dependent atrophy(P<0.001),however,there was no significant difference among each months of WT group(P>0.05).(3)The expression level of Aβ in the entorhinal cortex and hippocampus:Thioflavin-s stainning analysis showed that Aβ both in entorhinal cortex and hippocampus were expressed at the age of 6 and 12 months,and the deposition of Aβ at 12 months was significantly higher than that at 6 months(P<0.05).However,there was neither Aβ deposition in entorhinal cortex nor hippocampus of APP/PS1 and WT group mice aged 2 months.(4)Correlations between the volume of entorhinal cortex,hippocampus and learing and memory ability in APP/PS1 mice:The main findings of the correlation analyses were that in APP/PS1 mice the performance of spatial learning showed a significant negative correlation with volume of the entorhinal cortex and hippocampus(r=-0.729,P<0.001;r=-0.643,P<0.001),whereas the performance of spatial memory showed a significant positive correlation with volume of the entorhinal cortex and hippocampus(i=0.705,P<0.001;r=0.719,P<0.001).(5)Correlations between the levels of Aβ-deposition and volume of entorhinal cortex and hippocampus in APP/PS1 mice:The main findings of the correlation analyses were that there was a significant negative correlation between the number of amyloid plaques and the volume changes of the entorhinal cortex and hippocampus in APP/PS1 mice(r=-0.865,P<0.001;r=-0.885,P<0.001).Conclusions:The characteristic of brain atrophy in entorhinal cortex and hippocampus may provide possible imaging evidence for the experimental application and intervention study of the AD model mice;moreover,cerebral volume of the entorhinal cortex and hippocampus atrophy can well reflect the state of cognitive function of AD,and the pathophysiological basis of brain atrophy may be beta amyloid.