The Effect And Molecular Mechanisms Of Rescuing Cognitive Deficits By Inhibiting P38 MAPK/ATF2 Signaling Pathway In APPswe/PS1dE9 Mice

Objective: To investigate the effect and molecular mechanisms of rescuing cognitive deficits and regulating multiple distinct pathological process of Alzheimer's disease by inhibiting p38 MAPK/ATF2 signaling pathway in APPswe/PS1dE9 mice.Methods: six-month-old male APPswe/PS1dE9 mice and their wild-type littermates were randomized into WT+SB239063 treated group,WT control group,APPswe/PS1dE9+SB239063 treated group and APPswe/PS1dE9 control group.The treated groups received SB239063(dissolved in 3% DMSO at a dose of 15mg/kg)once per day by intraperitoneal injection,whereas the control groups received an equal volume of 3% DMSO once per day by intraperitoneal injection.Six weeks after the treatments,the spatial learning and memory ability of all mice were evaluated by the Morris water maze test,the levels of soluble and insoluble A?40,A?42 and soluble A? oligomers were detected with enzyme-linked immunosorbent assay(ELISA)kits,the expression of crucial enzymes and proteins associated with the APP processing pathway,tau hyperphosphorylation and synaptic impairments were tested with western blot method.Results: Compared with the APPswe/PS1dE9 control group,the escape latency in reaching the hidden-platform were significantly decreased(P<0.01),while the percentage of time spend in the target quadrant(P<0.05)and the frequency of crossing the platform(P<0.01)were potently increased in APPswe/PS1dE9+SB239063 treated group(P<0.01).Meanwhile,the levels of soluble and insoluble A?42(P<0.05),A?40(P<0.05)and soluble A? oligomers(P<0.01)were dramatically decreased in APPswe/PS1dE9+SB239063 treated group versus the control group.In addition,the expression of p-p38 MAPK(P<0.01),p-ATF2(P<0.01),p-APP(P<0.01),sAPP?(P<0.05),BACE1(P<0.01),PS1(P<0.01),p-tau(Thr205)(P<0.01),p-tau(Ser404)(P<0.01),p-GSK3?(Tyr216)(P<0.01),p-Cdk5(Tyr15)(P<0.01)in APPswe/PS1dE9 mice were markedly reduced by SB239063 treatment.Conversely,the expression of sAPP?(P<0.01),ADAM10(P<0.01),NEP(P<0.01),IDE(P<0.05),PSD-95(P<0.05),SYP(P<0.01)were significantly upregulated compared to the APPswe/PS1dE9 control group.Conclusion: Our findings demonstrate that inhibiton of p38 MAPK/ATF2 signaling pathway can reverse cognitive impairments in the APPswe/PS1dE9 mice by reducing the A? toxicity,preventing tau hyperphosphorylation and improving synaptic functions.This study highlights that inhibitor of p38 MAPK/ATF2 signaling pathway can play a neuroprotective role in multiple pathological processes of Alzheimer's disease and may be developed as a new therapeutic intervention for Alzheimer's disease.