| [Objective] Amyloid beta protein(Aβ) is generated from amyloid precursorprotein (APP) through amyloid metabolic pathway, which closely related to Alzheimer'sdisease (AD) with abnormal aggregation. Sleep deprivation affects cognitive function,APP transgenic mice with long-term sleep restriction appears pathological Aβdeposition, suggesting that sleep loss may affect APP metabolism pathway and involve inthe pathogenesis of AD. Under physiological conditions, APP mainly generate soluble αfragment(sAPPα) through the non-amyloid metabolic pathways of (APP) and play aphysiological protective effect. However, the clinical intervention studies through APPamyloid metabolic pathways did not get the expected results in recent years. It isnecessary to re-examine and study the correlation between sAPPα and sleep, as well asthe underlying protection mechanism in sleep deprivation animal models. To observe thechange of sAPPα and cognitive ability in a clinical intervention based on theimprovement of sleep promotion is likely to be a new intervention or therapeutic targetfor cognitive disorders.[Methods] This subject by setting the normal sleep-wake model and the modelof sleep deprivation, to observe the sleep-related changes of sAPPα and its potentialcognitive-protection role in the sleep deprivation model. Further more, to investigate thelevels of sAPPα in the cerebrospinal fluid (CSF) of Chronic insomniacs and AD patientsas well as its dynamics and related cognitive changes after drug intervention to insomnia.All rodents in relation to this subject underwent adapted feed for2weeks in special roomwith the simulative conditions of outside bright-dark change (12h:12h) to establishnormal sleep-wake cycle. First of all, to obtain CSF samples of Sprague-Dawley(SD)rats (built normal sleep-wake cycle) using the atlanto-occipital membrane puncturewithin24h time node (interval4h). To detect the levels of sAPPα in cerebrospinal fluidwith immunoblot technique (Western-blot) and to determine whether there is a circadianrhythm changes. Secondly, the experimental animals experienced12h sleep deprivation and12h recovery sleep, to obtain CSF samples at these two time points. The sameWestern-blot technique were performed to observe the changes of the sAPPα in SD ratsexperiencing acute sleep deprivation and restorative sleep as well as C57BL6miceundergoing sub-acute partial sleep deprivation. Third, to observe the effects by acutesleep deprivation on the levels of cognition (Morris water maze, spatial memory) and thelevels of sAPPα in the cortex and hippocampus in SD rats. Further more, to observewhether the intracerebral injection of recombinant sAPPα can improve affects of Morriswater maze spatial memory by sleep deprivation. Fourth, with measures of symptominquiry, physical examination, scale assessment to recruit the patients with AD andpatients with chronic insomnia, matching healthy control group. Cognitive rating scale,the PSG monitoring, and informed consent underwent lumbar puncture were performedin every group to obtain CSF samples. Then, to analyze the differences between thecognitive score, PSG data and CSF sAPPα. To administrate Eszopiclone3mg per day(2week) in patients with AD and patients with chronic insomnia, and to observe insomniasymptoms, corresponding cognitive score and levels of CSF sAPPα before and aftertreatment.[Results] Certain results listed below can be confirmed in this article.(A) Thelevels of sAPPα in CSF in SD rats fluctuate in natural sleep-wake cycle(p=0.013). Thepeak level of sAPPα in CSF present at point after sleep4h and the level of sAPPαdecrease gradually after awakening and maintain a relatively stable condition.(B) Thelevels of sAPPα in the CSF in SD rats decrease after12h of acute total sleep deprivation,and increased after12h of restorative sleep(p=0.024), and have a significant difference(p=0.011<0.05) comparing with environmental control.(C) Compared with the normalcontrol group and the environment control group, the levels of sAPPα in the cortex andhippocampus in C57BL6mice experiencing sub-acute partial sleep deprivation for twoweeks decline significantly(p<0.05), but the concentrations of sAPPα between the cortexand hippocampus have no statistically significant differences(p>0.05).(D) Sleepdeprivation can affect the SD rats in Morris water maze spatial memory (goal quadrant%) (p=0.000), intraventricular injection of recombinant sAPPα can improve spatial memoryimpairment (p=0.037), this improvement in more significant after the second injection (p=0.005).(E) Compared with healthy controls, AD patients and patients with chronicinsomnia have sleep efficiency lower (p=0.000), awakening during sleep increased(p=0.000) and REM sleep decreased (p=0.000); the AD patients awakening time isslower in patients with insomnia increase (p=0.018), and chronic insomnia patients withsleep latency was significantly prolonged (p=0.000).(F) The levels of sAPPα in CSF inAD patients decrease comparing with chronic insomniacs and healthy controls (p=0.000,p=0.000), however, between the two latters are no significant differences (p>0.05).(G) InAD patients, the levels of sAPPα in CSF have significant positive correlation(Spearman's rho0.676, p=0.016;0.935, p=0.000) with the cognitive scores and the sleepefficiency.(H) Eszopiclone intervention in the treatment of insomnia can be significantlyimproved PSG sleep parameters (p<0.05).(I) Eszopiclone intervention can improvechronic insomnia in patients with cognitive scale score (p=0.047), but does not changedoes not change the level of sAPPα in CSF (p=0.142); the intervention can be increasedthe levels of sAPPα in CSF in AD patients(p=0.004), but does not improve thecognitive scale score in AD patients (p=0.514).[Conclusion] First, APP showed rhythmic changes in normal sleep-wake state,reached a peak in the sleep period. Both acute total sleep deprivation or sub-acute partialsleep deprivation can lead to a decline in the level of sAPPα in brain, and the declineinduced by the acute sleep deprivation can be quickly corrected after recovery sleep,suggesting that sleep and brain's levels of sAPPα. Second, the intracerebral injection ofrecombinant sAPPα can counter the damage of acute total sleep deprivation of spatialmemory in animal models, this confrontation there may be dose-related. Third, the levelof sAPPα in AD CSF of patients with decreased cognitive scores and sleep time waspositively related to the same insomnia symptoms in patients with chronic insomniasAPPα levels were normal. The drugs interference with insomnia increase the levels ofsAPPα in CSF of AD patients, can not restore the cognitive assessment, however, the intervention for insomnia can improve cognition in patients with chronic insomnia score.There is a significant correlation between sAPPα and sleep, as well as cognitive function.In Alzheimer's disease, cognitive impairment has been formed, just sleep improvementcan not reverse cognitive deficits.
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