Estrogen-related Receptor Alpha Is Involved In Alzheimer's Disease-like Pathology

Objective:To investigate the expression of orphan nuclear receptor estrogen-related receptor a(ERRa)in APP/PS1 AD model mice and to explore the relationship between ERRa and Alzheimer's disease(AD).Methods:Western blot,immunohistochemistry and quantitive-PCR were used to detect the expression of ERRa protein and mRNA in the cortex and hippocampal brain tissue of AD and WT mice at age of 6,12 and 18 months.HEK-293 cells stably expressing human full-length APP sequence were transfected with ERRa plasmid or ERRa shRNA to over-express or knockdown it,thus effecting the expression of APP metabolic pathway-associated proteins and Tau phosphorylation,which can also be observed with the treatment of 50?M H2O2.Results:In APP/PS1 mice,an animal model of AD,ERR? protein and mRNA were decreased in a region-and age-dependent manner.In HEK293 cells that stably express human full-length ?-amyloid precursor protein(APP),overexpression of ERRa inhibited the amyloidogenic processing of APP and consequently reduced A ? 1-40/1-42 level.ERRa overexpression also attenuated Tau phosphorylation at selective sites,with the concomitant reduction of glycogen synthase kinase 3 ?(GSK3?)activity.Interestingly,alterations of APP processing and Tau phosphorylation induced by hydrogen peroxide were reversed by ERRa overexpression in HEK/APP cells.Conclusions:These results indicated that ERRa plays a functional role in AD pathology.By attenuating both amyloidogenesis and Tau phosphorylation,ERRa may serve as a potential therapeutic target for AD.