A Preliminary Study On The Mechanism Of Sleep Disorder In Presenilin1/2 Double Knockout Mice

Dementia is a broad category of brain diseases that continually cause the learning and recognition disability,and other common symptoms include emotional problems,language problems and the decrease of motivation,which signaificantly affect patients'daily life quanlity.The most common type of dementia is Alzheimer's disease(AD),a multifactorial disease associated with age,and till now there are no effective therapeutics to prevent or cure the devastating memory impairment associated with the disease.More and more evidence indicates that there is a close association between AD and sleep disorders,and up to about 45%of AD patients show sleep disorders,and the proportion increase with the intensification of the disease,but the mechanism of sleep changes associated with AD is poorly understood yet.In addition,whether the improvement of sleep could improve neurodegenerative symptoms of AD remains obscure.In this study,we investigated the sleep disorder,behavioral characteristics and molecular mechanism in Presenilins1/2 knockout mice(DKO mice),which are regarded as the appropriate dementia mice model,DKO mice showed disruption of sleep-wake pattern and circadian rhythms.The NREM sleep of three-month old DKO mice was decreased,and the REM sleep was more severely affected with the increase of the month age.The results of c-fos immunohistochemistry showed that the c-fos positive cells were fewer in SCN and VLPO,and higherin TMN in the DKO mice during light period,which suggests a marked increase in wakefulness in DKO mice.By fluorescent quantitative PCR,we found that the expression of NPAS2,A1R,MAO-A decreased significantly in the hypothalamus of DKO mice compared with WT mice,which might contribute to the sleep disorder in DKO mice.Finally,to seek the possibility of rescue the sleep disorder in DKO mice,we applied Trazodone to two-month old DKO mice for two months.Then a serial of behavioral experiments including wireless wheel running,open field test,elevated O maze test,tail suspension test,Morris' water maze test and novel object recognition test etc.were performed to evaluate the phamacological effect of Trazodone on DKO mice.Unfortunately,the results showed that Trazodone failed to rescue the hyperlocomotion as well as the learning and momery deficiency in DKO mice.While more detailed analysis remains to be further performed.To sum up,we systematically analyzed the sleep and circadian rhythms disorders in DKO mice,which provides a uniquely powerful tool for studies on the pathophysiology of and treatments for sleep deficits and A-beta independent abnormalities in neuro-degernerative diseases.