The Beneficial Effects Of Rutin On AD Transgenic Mice And The Development Of A Promising Mouse Model For Safety Evaluation Of AD Immunotherapeutic Agents

Alzheimer's disease(AD)is a progressive,neurodegenerative disease characterized by extracellular P-amyloid(A?)plaques and intracellular neurofibrillarytangles in the brain.Abeta aggregation is closely associated with neurotoxicity,oxidative stress,and neuronal inflammation.The soluble A? oligomers are believed to be the most neurotoxic form among all forms of A? aggregates.In the current study,we investigated the effect of rutin on APPswe/PS1dE9 transgenic mice.Results demonstrated that orally administered rutin significantly attenuated memory deficits in AD transgenic mice,decreased oligomeric A? level,increased super oxide dismutase(SOD)activity and glutathione(GSH)/glutathione disulfide(GSSG)ratio,reduced GSSG and malondialdehyde(MDA)levels,downregulated microgliosis and astrocytosis,and decreased interleukin(IL)-1? and IL-6 levels in the brain.These results indicated that rutin is a promising agent for AD treatment because of its antioxidant,anti-inflammatory,and reducing A? oligomer activities.Active immunotherapeutics have been hot investigational areas for AD treatment.The vaccine AN1792 using pre-aggregated A?42 as immunogen showed beneficial effects of removing amyloid deposits and slowing cognitive decline in AD transgenic mice.However,the clinical trial was halted because 6%of the patients developed meningoencephalitis.Hence it is very important to develop an effective and sensitive mouse model for testing the potential adverse effects of the AD treatment agents.In our previously study,we cross-bred EAE model mouse and APPswe/PS1de9 mouse to generate a new mouse model EAE/AD.Afther vaccinated with AN1792,EAE/AD mice showed significant and extensive T-cell mediated neuroinflammation in the brain in this research.Our immunohistochemical results demonstrated that,AN 1792 immunization increased microhemorrhage,caused T-cells infiltration,upregulated microgliosis and astrocytosis,increased A? deposition,and enhanced TNF-a,EL-1? and IL-6 production in the brain of EAE/AD mice.These findings indicated that EAE/AD mouse is a promising animal model of safety evaluation for AD treatment agents.