Lithium Chloride Improves The Learning And Memory Ability Of APP/PS1 Double-transgenic Mice By Reduce The Levels Of Oxidative Stress

Objective:Lithiumhaspotentialneuroprotectiveeffectson neurodegenerative disease,however the molecular mechanism of Lithium need further elucidation.In the pathogenesis of Alzheimer's disease(AD),higher levels of oxidative stress(OS)and excessive production of?-Amyloid peptide(A?)both are important pathogenic factors that could lead to dementia.In present study,we focused on the expression level of superoxide dismutase 2(SOD-2)and silent information regulator 3(SIRT3),which are related to OS,in various regions of the postmortem brains from the AD patients;This study also investigate whether the treatment of Lithium chloride(LiCl)could reduce the amount of A?in brain tissues of APP/PS1double-transgenic mice,and whether LiCl could regulate GSK3?/Nrf2/HO-1 pathway to reduce the injury of OS and alleviated the decline of learning and memory degeneration in APP/PS1 double-transgenic mice.Methods:Ten postmortem brains from the AD patients were used and various brain regions,such as the temporal and frontal cortices,hippocampus and cerebellum.Brains in the same regions from the age-matched-non-AD health people were selected as control.The expression levels of SOD-2 and SIRT3 in brain tissues of the AD patients and the number of senile plaques in brains were determined by immunohistochemical method.Expression intensity correlation of SOD-2 and SIRT-3 in various regions of brain were analyzed with the Spearman correlation test.PCR were performed to identify the DNA mutations of the double-transgenic mice.APP/PS1 double transgenic and wild-type(WT)mice were divided randomly into 4 groups,namely,WT,WT+LiCl,the transgenic+LiCl and the transgenic groups.The mice in the groups of WT+LiCl and the transgenic+LiCl were treated with LiCl at 4 or 8 months(100mg/kg,one time a day for 2 months),whereas the mice in the groups of WT and transgenic were gavaged with saline of the same volume.The protein abundance of phospho-GSK3?(ser9),Nrf2 and HO-1 were detected by western blot analysis.The activities of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px),and the content of malondialdehyde(MDA)in serum and brain tissues were measured by relating detection kits.The contents of insoluble A?in brain tissues were determined by ELISA.Nissl bodies in brain regions were examined by Nissl staining.The behavioral changes of learning and memory capacity of mice were determined by Morris water maze.Results:The numbers of SOD-2 and SIRT3-positive neurons and integrated optical density of immunohistochemical staining for these proteins in the temporal,frontal cortices,and hippocampus of AD patients were significantly decrease than those in corresponding controls.In the case of the cerebellum,weak expression of SOD-2 and SIRT3 were observed in granule cells,with no significant difference between AD and the control groups.Interestingly,the protein levels between SOD-2and SIRT3 were significantly correlated in neurons in all regions of the investigated AD brains(r~2=0.425,P=0.041;r~2=0.411,P=0.046;r~2=0.402,P=0.049)except the cerebellum(r~2=0.031,P=0.624).Compared with WT mice,the visible senile plaques and the increased insoluble A?were observed in the brain tissues of APP/PS1 double transgenic mice at 6-and 10-months of old,which was especially true at 10 months(P<0.05),the activity of GSK3?was significantly increased and the expressions of Nrf2 and HO-1 proteins were decreased(P<0.05),the activities of SOD and GSH-Px were decreased as well as the content of MDA were increased in serum and brain tissues of APP/PS1 double transgenic mice(P<0.05),and the decreased Nissl bodies in neurons of the brains and ability of learning and memory were observed in mice with APP/PS1 mutation as compared to WT.When the APP/PS1 double transgenic mice at 4 or 8 months of age were treated with LiCl by gavage for 2 months,the numbers of senile plaques and the contents of insoluble A?were significantly decreased than those of the untreated APP/PS1 mice(P<0.05).At the same time,the changes of the activity of GSK3band the expression levels of Nrf2 and HO-1 in brain tissues of the APP/PS1 transgenic mice were attenuated and the levels of OS in serum and brain tissues of the transgenic animals were decreased(P<0.05),as well as the density of Nissl bodies was significantly increased and the spatial learning and memory ability of the mice was improved(P<0.05).Conclusion:The express levels of SOD-2 and SIRT3 in various regions of AD patients and the activities of SOD and GSH-Px of APP/PS1 double transgenic mice were significantly decreased,as well as the increase of the amount of MDA in serum and brain tissues of APP/PS1 double transgenic mice,which may indicated the level of OS in AD patients and animal was increased than those corresponding controls.The treatment of LiCl can reduce the content of A?in brain tissues of APP/PS1 double-transgenic mice,and can reversed the raised level of OS and the damages of neurons in the mice with APP/PS1 genetic mutation,the mechanism of which may involve in the down-regulation of the activity of GSK3?and consequently enhance the expressions of Nrf2 and HO-1.Thus,to play the role of neuroprotective and improves the learning and memory ability of transgenic mice.