The Effect And Possible Mechanism Of PrP~c Involved In Cognitive Impairment Induced By Sleep Deprivation

?Objective? Now,the phenomenon of sleep disorders is more and more common in social people.Sleep disorders was considered as one of the clinical symptoms of Alzheimer's diseases(AD)in the past time.However,Some investigators think that sleep disorders is not only the clinical symptoms of AD,but also the risk factor of AD,But,the underlying mechanisms remains undefinitely.Cellular prion protein(PrP~C)is a depth conservative membrance protein,which is a membrane-bound glycoprotein attached to the cell surface by a GPI anchor.it is present at highest levels in neurons of the brain and spinal cord.much less is known about the physiological function of PrP~C.Previous studies indicate PrP~C play an important role in the regulation of sleep and the formation and consolidate of memory.The present study has detected a remarkably synchronous circadian rhythm in PrP~C mRNA at various sites in the mice forebrain,which prompts a possible that there is asynchronous circadian rhythm in PrP~C.Previous studies strongly indicate PrP~C inhibits the ?-secretase(BACE1)cleavage of APP and reduces A? formation.Otherwise,sleep deprivation can induce cognitive impairment has been confirmed in previous studies.Therefore,we suspect that PrP~C has underlying neuroal protection and maybe correlated with cognitive impairment induced by sleep deprivation.It is important to observe the role of PrP~c in the function of cognitive impairment induced by sleep deprivation,and it is possible to find potential therapeutic targets for cognitive disorders.?Method? In this study,C57 B L /6 mice were randomly divided into 6 groups according to body weight,normal feeding for 2 weeks,establishment of normal sleep-wake cycle.The mice were sacrificed at 6 different time points in 24 h to obtain the samples of hippocampus and cortex,the expression of PrP~c and A? was detected by ELISA method to determine whether there was circadian rhythm change.Secondly,C57 B L /6 mice were randomly divided into three groups according to body weight: blank control group(CC),environmental control group(EC),sleep deprivation group(SD),after 72 h sleep deprivation by modified multiple platform method,the mice were sacrificed to obtain hippocampal tissue,and the expression of PrP~C was detected by Western Blot and A? was detected by ELISA,to observe the effect of sleep deprivation on PrP~c and A? in hippocampus of mice.Thirdly,PrP~c overexpression of adeno-associated virus was injected into the hippocampus of mice by brain stereotactic injection,to observe whether PrP~c overexpression can improve the spatial memory impairment induced by sleep deprivation in mice.?Result? The results of this study show that(1)There were statistically significant changes in A? in the brain of C57 B L /6 mice at 6 different time points in the 24-hour normal sleep-wake cycle(P<0.05);the results of single cosine analysis show that PrP~C has circadian rhythm in the cortical site(F = 11.22,P <0.05),A? had circadian rhythms in the hippocampus,(F = 26.72,P <0.05).(2)Changes of PrP~C expression in hippocampus after sleep deprivation: the PrP~C expression of sleep deprivation group(0.22 ± 0.05)was obviously reduced,compared with cage control group(0.64 ± 0.16)and environmental control group(0.58 ± 0.09),the difference was statistically significant(F = 4.366,P <0.05);The expression of A? was significantly higher in the sleep deprivation group(13.03 ± 0.71)than in the control group(8.22 ± 0.8)and the environmental control group(8.6 ± 0.57),the difference was statistically significant(F = 14.511,P <0.05).(3)Injection of PrP~c in the hippocampus by overexpression of the adeno-associated virus group can improve the hippocampal spatial memory impairment induced by sleep deprivation.The percentage of the target quadrant was higher in the overexpression group than in the control group,the difference was statistically significant(F = 6.196,P = 0.002).?Conclussion?First,the level of PrP~C expression shows circadian rhythm in the normal sleep-wake cycle,and the peak appears in the awakening period,and REM sleep deprivation can lead to decreased PrP~C expression in mice hippocampus,which suggesting that the PrP~C expression levels of brain associated with sleep-wake cycle.Secondly,PrP~C overexpression in the mice hippocampus can improve memory impairment induced by REM sleep deprivation.