The Protective Effect Of Tenuigenin On Alzheimer's Disease By Enhancing Nrem Sleep And Its Mechanism

Background: The aggregation and deposition of ?-amyloid(A?)is a cardinal neuropathological hallmark of Alzheimer's disease(AD).Emerging evidence indicates that sleep disruption is highly prevalent in AD and prolonged wakefulness may increase the accumulation of A? in brain.Sleep may play an important role in AD disease pathology and progression.Targeting the sleep–wake cycle and improving sleep may be an effective way in the treatment of AD.Tenuigenin,a traditional Chinese medicine,has the effect of promoting sleep and tranquilization.However,it is unknown whether tenuigenin inhibits A? pathological by sleep-enhancing effects in AD.Methods: The sleep-wake cycle of APP/PS1 mouse model and the hypnotic effects of tenuigenin were assessed by electroencephalographic(EEG)and electromyographic(EMG)analysis.After tenuigenin was intraperitoneally administered for 7 weeks in APP/PS1 transgenic mice,A? plaques and A? 42 levels were measured by immunohistochemistry and enzyme-linked immunosorbent assay.After tenuigenin was intraperitoneally administered accompanied sleep deprivation(SD)for 5 weeks in APP/PS1 transgenic mice,Plaque load and A? levels were determined.The level of amyloid precursor protein(APP)and p-APP were quantified by western blot.Results: APP/PS1 mice increased wakefulness by 38.4%(P<0.01)in 12-h light phase,17%(P<0.05)in 24-h totally.Tenuigenin administration promotes the sleep time of APP/PS1 mice,an analysis of amount of each stage in 9 h after administration of tenuigenin showed that tenuigenin increased NREM sleep by 53.73% in APP/PS1 transgenic mice(P<0.001).After tenuigenin was intraperitoneally administered for 7 weeks in APP/PS1 transgenic mice,we found tenuigenin treatment ameliorated spatial memory deficits and significantly decreased the level of A? 42 in the brain(P < 0.001).In addition,TEN significantly reduced amyloid plaques areas in the brains of APP/PS1 mice(P<0.001).After tenuigenin was intraperitoneally administered accompanied sleep deprivation(SD)for 5 weeks in APP/PS1 transgenic mice,the level of A? 42 and amyloid plaques areas in the brain was increased in TEN-SD group when compared with TEN-NSD group.Furthermore,we found that APP and p-APP(pThr668)levels were significantly reduced in the APP/PS1 mice after tenuigenin treatment.We also evaluated sleep deprivation on the metabolism of A? in tenuigenin treatment APP/PS1 mice.We found that APP and p-APP levels were restored in tenuigenin treatment APP/PS1 mice after sleep deprivation.Conclution: Our results demonstrate that tenuigenin exerts the enhance-sleep effects on APP/PS1 mice and prevent A? pathological via enhance-NREM sleep effects,suggesting that tenuigenin may be feasible for the treatment of AD.