Icariin improves APP/PS1 mice's cognitive function through reducing endoplasmic reticulum stress and apoptosis

摘要

OBJECTIVE Alzheimer disease(AD) is a progressive neurodegenerative disorder involving a gradual decline in many cognitive processes and in neurons.The endoplasmic reticulum(ER) is involved in several crucial cellular functions,eg protein folding and quality control.Massive misfolded or unfolded proteins in ER can disturb the function of ER and induce ER stress,which results in neuronal death in AD.Icariin(ICA) has a wide range of neuro protection and has been researched in AD treatment.However,whether ICA has the effect on ER stress in AD condition,and how ICA affects ER stress remains stil unclear.Therefore,the current study aimed to investigate the mechanism of ICA against cognitive impairments in AD model through ER stress pathway and apoptosis.METHODS Twelve months male APP/PS1 or wild-type(WT)mice were randomly divided into four groups:APP/PS1,and APP/PS1+ICA,WT and WT+ICA groups.The treated mice were given ICA60 mg·kg-1 per day and control mice were received the same volume distilled water for consecutive 3 months.The Morris water maze and novel object recognition were used to detect animals′ behavior.Nissl staining was used to observe the neuronal morphology in hippocampus area.The protein and(or) phosphorylation level of GRP78,p-PERK,PERK,p-IRE1,IRE1,ATF6,p-e IF2α,eIF2α,ATF4,CHOP,the level of cleaved-casepase 3,Bax and Bcl-2 were examined by Western blotting.RESULTS The behavior performance testing by Morris water maze and novel object recognition deteriorated in APP/PS1 mice compared with WT mice,however,ICA significantly improved the behavior performance when compared with APP/PS1.The neuron impairments in APP/PS1 mice also were ameliorated after ICA treatment.The protein expression of GRP78,ATF4,CHOP,and the level of p-PERK and p-eI F2α were higher in APP/PS1 mice than that in WT mice.The Bax/Bcl-2 ratio elevation and caspase 3 activation have been found in APP/PS1 mice.After treated with ICA,those above-mentioned parameters were decreased compared with APP/PS1.However,the levels of IRE1,p-IRE1 and ATF6 were not change among other groups.CONCLUSION ICA may decrease the ER stress and apoptosis in AD model,and may be through inhibiting the PERK/eI F2α pathway,not IRE and ATF6 pathways.