Activating Transcription Factor 6 Reduces Toxic Aβ1-42 And Restores Memory In Alzheimer’s Disease Model Mice

BackgroundAccording to the statistics,there are approximately 9.83 million people with Alzheimer disease among people aged 60 in China.AD presents a huge burden in the gradually aging society.As a neurodegenerative disease,the main symptoms of AD are progressive,irreversible memory loss and cognitive disability.At present,the medicine used for clinic treatment could not prevent or reverse the course of AD and only aimed for symptomatic treatment,therefore needed to be further studied by researchers.Exploring the AD’s pathogenesis is of great significance for novel drug treatments of AD.Endoplasmic reticulum stress plays a crucial role in the progression of many neurodegenerative diseases,such as Huntington’s disease and Parkinson’s disease.By activating the UPR pathway,endoplasmic reticulum stress is able to reduce erroneous protein synthesis,promote chaperone protein synthesis and protein degradation.The UPR pathway consists of three signaling pathways,namely IRE1α,PERK,and ATF6 signaling pathway.Our previous study has found that the expression of ATF6 was reduced in the brain of APP/PS1 mice(AD model mice).In a variety of neurodegenerative diseases,the expression level of the H2S-producing enzyme CTH was lower than that of the control group.As stated by our earlier research,ATF6 regulated the expression of CTH at the transcription level.This research first analyzed the expression level of ATF6 and CTH in the brain of AD patients,then continued to explore the mechanism of ATF6 regulating CTH.In the end,this study explored the effects of ATF6 and CTH on the spatial learning ability and memory level of APP/PS1 mice.Based on the former research work,this study further linked ATF6 and CTH with the occurrence and development of AD,and provided new perspectives for exploring the molecular mechanism of AD.MethodsImmunohistochemistry was used to detect the expression levels of ATF6 and CTH in AD cases and control groups;dual luciferase reporter gene experiment was employed to verify that ATF6 regulates ATF/CRE site on the CTH promoter,the "tg" sequence activity in 293T cells;the EMSA experiment was used to explore whether ATF6 can directly bind to the "tg" sequence to regulate its activity;the Morris water maze and the Y maze were applied to explore the effect of ATF6 knockout in the AD model mice APP/PS1 mice;ATF6-/-/APP/PS1 mice were injected with a lentivirus carrying CTH sequence into the lateral ventricle.Three months later,behavioral experiments,the Morris water maze and Y maze were employed to test the spatial learning ability and memory level of the mice;Western blot were utilized to detect the expression of CTH in the mice.ResultsThe expression levels of ATF6 and CTH in the cortex and hippocampus of AD cases were lower than those in the control group;ATF6 directly bound to the "tg" fragment on the CTH promoter to regulate its transcriptional activity.Compared with the APP/PS1 mice,the spatial memory and learning ability of ATF6/-/APP/PS1 mice were decreased.Injecting CTH lentivirus into the lateral ventricle of mice was able to alleviate the spatial memory loss and declined learning ability of APP/PS1 mice due to the decrease of ATF6 expression.ConclusionATF6 is able to affect the spatial learning and memory ability of Alzheimer mice by regulating the transcriptional activity of CTH.