The Effect Of Autophagy In Sevoflurane-induced Spatial Memory Deficit In APP/PS1 Transgenic Mice

Background:AD is the most common cause of senile dementia.Characteristic clinical manifestations of AD is progressive decline in cognitive function.The accumulation of intracellular A?and the formation of extracellular A?plaque are the most important pathological changes.Laboratory studies have found that anesthetics can increase A?level and cognitive dyfunction,which suggest that anesthesia induced cognitive dysfunction may share some similar molecular mechanisms with AD.Autophagy is an important degradation mechanism in cell.If autophagy function impaired,the volume of autophagic lysosomes increased and the A?accumulat in neuron,which promote the pathological progress of AD.Our previous studies have shown that 4h 3%sevoflurane anesthesia causes cognitive dysfunction in APP/PS1 mice.In this study we mainly discusses the effect of autophagy in sevoflurane induced spatial memory Deficit.Methods:APP/PS1 transgenic AD modle mice of 6 months were randomly divided into4 groups including control,sevoflurane?Sevo?,rapamycin?Rap?and Rap+Sevo.Three weeks before anesthesia,the mice in the RAP group and Rap+Sevo group were injected with rapamycin intraperitoneally twice per day,and the mice in the Control group and Sevo group were injected with vehicle.24 h after the last injection,the mice in the Control group and Rap group were treated by inhaling with 60%oxygen while the mice in the Sevo group and Rap+Sevo group were subjected to inhaling 60%oxygen+3%Sevoflurane for 4 h.The brain tissue were acquired 24 h after anesthesia treatment?n=5?,following by immunofluorescence to detect colocalization of LC3 and LAMP1or CathD,which was used to observe the autophagy accumulation level and morphology of autophagy-lysosome in CA1 region of hippocampal.In addition,Western-blot was used to detect the expression of LC3?,p62,CathD and?-CTF,whereas the level of A?₄₀ and A?₄₂ were observed by ELISA.The brain tissue were acquired 7days after anesthesia treatment?n=5?,following by immunofluorescence to detect the number and area of A?plaque in the hippocampal.Meanwhile the spatial learning and memory ability were determined by Morris water maze?n=10?.Results:24h after anesthesia,the expression of intracellular?-CTF and A?40 in the Sevo group were increased as comparing with Control group,and LC3 and LAMP1 as well as CathD were colocalize,accumulation of large intracellular autophagy lysosome was observed?D>1 um?,in addition,the level of p62 were also upregulated while CathD was repressed.Interestingly,the autophagy-lysosome in the hippocampal of group Rap+Sevo was almost abolished as comparing with Sevo group,and the expression of?-CTF,p62,A?40 as well as A?42 was suppressed,however,there was no change in the level of CathD.7 days after anesthesia,the level of extracellular A?plaque were decreased in the Sevo group as comparing with Control group,and the spatial learning and memory ability was significantly impaired.Meanwhile,the spatial learning and memory ability was significantly promoted in Rap+Sevo group when comparing with Sevo group,and the the number and area of extracellular A?plaque were decreased.But of note,Rap alone did not improve the learning and memory ability compared to Control group.Conclusion:After sevoflurane anesthesia,the hippocampal tissue of AD mice showed large autophaglysosomal and accompanied with the decline of autophagy degradation,the accumulation of A?and the decrease of spatial learning ability.It can significantly improve the cognitive function of mice after rapamycin treatment by removing the large autophagic lysosomes and increasing the efficiency of autophagy.