Intervention Effect And Mechanism Of Two Selenium Compounds On Alzheimer’s Disease

Objective: Alzheimer’s disease(AD)is a neurodegenerative brain disease with an insidious onset.The exact cause of AD is not clear so far,and it can not be completely cured at present,which caused tremendous pressure on families and the society.It is urgent to seek effective drugs for AD.Our previous study have showed that Se-methylselenocysteine(SMC)could significantly improve the behavioral cognition and related pathological disorders in the triple transgenic mouse model of AD.Thus,in this study,we further investigated the molecular mechanism of SMC intervention in AD by proteomics technique.In addition,we selected another organic selenium compound,Ebselen,to study its therapeutic effect on AD mice and explore the molecular mechanism,especially its protective effect on mitochondrial damage in AD mice.Methods: Morris water maze,open field(open box)test,elevated plus-maze and Y-maze were used to test the learning ability,tension,anxiety and spatial memory of mice.The effect of SMC on the proteome of 12-month-old mice was analyzed by i TRAQ technique.The effects of SMC and Ebselen on the expression levels of pathologically related proteins in the brains of mice were detected by Western Blot.The effects of SMC and Ebselen on the structure and morphological mitochondria and synapse in the mice were observed by transmission electron microscope.Results: Behavioral experiments showed that SMC and Ebselen could significantly reverse the behavioral and cognitive impairment of AD mice.Proteomic analysis showed that 181,271 and 41 proteins were found as the differentially expressed proteins(DEP)between AD/WT,AD + SMC/AD and AD + SMC/WT groups,respectively.Among them,138 proteins in AD group were reversed by SMC treatment.DEPs in AD/WT group and AD + SMC/AD group were mainly related to metabolism,synapse and antioxidant proteins,which were reduced in AD mice and up-regulated by SMC treatment.In addition,we also found that the ATP level in thebrain of AD mice was reduced and the synaptic structure was destroyed,which were significantly improved after SMC treatment.For Ebselen,we found Ebselen could effectively remove the Aβ oligomer in the brains of AD mice.Meanwhile,ebselen ameliorated mitochondrial damage in AD mice,including the improvement of the energy metabolism,biogenesis,and fission and fusion balance.In addition,through transmission electron microscopy,we found the structure of mitochondria and synapses in AD mice was damaged,which were also repaired with the treatment of three different doses of Ebselen.Conclusion: SMC and Ebselen improved the learning and memory,exploration ability and alleviated anxiety of AD mice,significantly reversed damaged mitochondria and synapses in the brains of AD mice and reduced the generation of oxidative stress,which may be the common underlied intervention mechanism of selenium compounds in AD.