Involvement Of P38MAPK/GSK3Signaling And Neuropeptide VGF In The Regulation Of Cognitive Dysfunction And Depressant-like Behaviors Induced By Soluble Beta Amyloid Protein1-42Oligomers In Mice

Objective1. In order to clarify the relationship of the cognitive deficits and depressive-like behaviorsbetween the dysfunction of p38MAPK/GSK3signaling induced by soluble beta amyloid protein1-42oligomers,the effects of p38mitogen-activated protein kinases inhibitor SB203580on the memory deficits anddepressive-like behaviors and dysfunction of p38MAPK/GSK3signaling in hippocampus and cortex of miceinduced by Aβ1-42was demonstrated.2. The effect of SO Aβ1-42microinjected into the CA1and DG regions ofhippocampus on cognitive deficits and depressive-like behaviors of mice and on the expression of neuropeptideVGF,which is novel etiopathogenesis and therapeutic target of AD and depression.Experiment1: The effects of p38MAPK inhibitor SB203580on the behaviors and dysfunction ofp38MAPK/GSK3signaling induced by SO Aβ1-42.Methods Adult male ICR mice were positioned in a stereotaxic instruments with Aβ1-42or salineadministrated into bilateral CA1regions of the dorsal hippocampus to make Alzheimer’s disease (AD)model.24hours after the infusion of Aβ1-42, SB203580or PMA were administered (i.p.) daily. The micewere divided into seven groups: A[control], B[SO Aβ1-42treated group], C[SO Aβ1-42+SB203580(0.5mg/kg) group], D[SO Aβ1-42+SB203580(1mg/kg) group], E[SO Aβ1-42+SB203580(2mg/kg) group],F[SO Aβ1-42+SB203580(4mg/kg) group], G[SO Aβ1-42+SB203580(2mg/kg)+PMA (0.2mg/kg)group].12days after the microinfusion of Aβ1-42, the behavioral tests were conducted1hour after the drugtreatment, including novel object recognition test(NOR), morris water maze test(MWM), forced-swimtest(FST) and tail-suspension test(TST).24after all the behavioral tests, the mice were sacrificed andp-p38MAPK, p-CREB, CREB, GSK3and the different phosphorylation in the hippocampus and cortexwere detected. Behavioral data analyzed by GraphPad Prism5software, quantity of protein expressionusing Odyssey V3.0software and GraphPad Prism5software.Results1. The recognition index were significantly decreased by Aβ1-42microinjected into the CA1subregions of hippocampus, meanwhile, the immobility time were significantly increased in mice. Whileonly the dose of2mg/kg of SB203580significantly reversed the memory deficits induced by SO Aβ1-42,both the dose of2and4mg/kg of SB203580significantly decreased the immobility time of depressive-likebehaviors in mice. However, above effects of SB203580was significantly interdicted by PMA.2.Consistent with the behavior test, the expression of p-p38MAPK was significantly increased, and theexpression of pCREB and p-Ser9-GSK3β were significantly decreased in hippocampus. In addition, boththe dose of2and4mg/kg of SB203580significantly reversed all of the changes of above the expression ofproteins. Similarly, above effects of SB203580was significantly interdicted by PMA. However, alltreatments did not change the expression of CREB, p-Tyr279-GSK3α, p-Tyr216-GSK3β andtotal-GSK3α/β in hippocampus of mice. Further, all of the proteins expression had no significantly changesin cortex of mice.Experiment2: The effects of SO Aβ1-42microinjected into the CA1and DG regions ofhippocampus on memory deficits and depressive-like behaviors of mice and on the expression ofneuropeptide VGF.Methods Ault male ICR mice were positioned in a stereotaxic instruments with differentconcentrations of Aβ1-42or Aβ42-1or saline administrated into bilateral CA1or DG regions of the dorsalhippocampus to make AD model. The mice were divided into eight groups: H[DG control], I[DG Aβ42-1treated group], J[DG Aβ1-42(0.5μg/side) group], K[DG Aβ1-42(1μg/side) group], L[CA1control], M[CA1Aβ42-1treated group], N[CA1Aβ1-42(0.5μg/side) group], O[CA1Aβ1-42(1μg/side) group].12days after theoperation, the behavioral experiments were performed.24after all the behavioral tests, the mice were killed and neuropeptide VGF in the hippocampus were detected. Behavioral data analyzed by GraphPad Prism5software, quantity of protein expression using Odyssey V3.0software and GraphPad Prism5software.Results1. The results of the mice treated with Aβ1-42in DG or CA1subregions of hippocampus weresimilar. The dose1μg/side injected into the DG or CA1subregions of hippocampus significantly decreasedthe recognition index and increased immobility. But only in DG subregion of hippocampus, both two dosesof Aβ1-42significantly increased the immobility in FST and TST.2. Consistent with the behavior test, all thegroups treated with Aβ1-42significantly decreased the expression of neuropeptide VGF compared with thecontrol group or Aβ42-1treated group.Conclusion The dysfunction of p38MAPK/GSK3signaling may involve in the regulation of memorydeficits and depressive-like behaviors induced by SO Aβ1-42. In addition, the closely relationship of neuropeptideVGF and memory deficits and depression-like behaviors induced by SO Aβ1-42shown that neuropeptide VGFplay an important role on the progress of AD and depression.