Sodium Selenate Inhibits The Molecular Mechanism Of ?-amyloid Production And Olfactory Bulb Lesions In Hippocampus Of Alzheimer's Disease Model Mice

Alzheimer's disease(AD)is an age-related progressive neurodegenerative disease,initially with progressive loss of memory and acquired knowledge,and ultimately with the loss of the ability for daily life,which brings a heavy burdento both the society and thefamily.Accumulating evidences show that selenium dietary intake is inversely associated with the mortality of Alzheimer's disease(AD).Sodium selenate has been reported to reduceneurofibrillarytangles(NFT)in the tauopathic mouse models,but its effects on the Wnt/?-catenin signaling pathway and amyloid protein precursor(APP)processing remain unknown during AD formation.In this paper,triple transgenic AD mice(3×Tg-AD)had been treated with 6 ?g/ml sodium selenate in drinking water for 10 month before the detection of hippocampal pathology.Increased A? generationand neuronal apoptosis were found in the hippocampus of AD model mouse.Down-regulation of Wnt/?-catenin signaling is closely associated with the alteration of AD pathology.Treatment with sodium selenate significantly promoted the activity of protein phosphatases of type 2A(PP2A)and repressed the hallmarks of AD.Activation of PP2 A by sodium selenate could increase active ?-catenin level and inhibit GSK3? activity in the hippocampal tissue and primarily cultured neurons of AD model mouse,leading to activation of Wnt/?-catenin signaling and transactivation of target genes,including positively-regulated genes c-myc,survivin,TXNRD2 and negatively-regulated gene BACE1.Meanwhile,APP phosphorylation was also reduced on the Thr668 residue after selenate-treatment,causing the decreases of APP cleavage and A? generation.These findings reveal that the Wnt/?-catenin pathway is a potential target for prevention of AD and sodium selenate may be developed as a new drug for AD treatment.In addition,the early pathology of AD has been reported to be olfactory dysfunction.In order to explore the effect of sodium selenate on the change of olfactory bulb in AD model mouse,two-month-old triple transgenic AD model mice weretreated with 3?g/ml sodium selenate in drinking water for 4 months.The results showed that sodium selenate significantly increased the spatial memory ability of mice.Compared with the non-transgenic mice,olfactory bulb A? and Tau-pS231 expression levels in AD mice were significantly increased,while these expression levels were significantly decreased in AD mice treated with sodium selenate.The expression levels of genesGrin2 a,Grin2b,Creb1,Gng13 and Chrm2 were up-regulated by the treatment with sodium selenate,while the gene Gfap was down-regulated.Further experiments confirmed that the synaptic-related genes Grin2 a and Grin2 b had similar results of transcriptome.In order to verify this result at the cellular level,primary neurons isolated from olfactory bulb of AD mice were treated with sodium selenate and the expression level of synaptophysin was found to be increased.In conclusion,sodium selenate activated the Wnt/?-catenin signaling pathway which was inhibited in the AD model mice.It also reducedneuronal apoptosis and A? generation.Meanwhile,sodium selenate could reduce A? production and tau hyperphosphorylation and promote the expression levels of Grin2 a and Grin2 b genes in the olfactory bulb of AD mice,leading to the increase of the synaptic plasticity.