Estrogen-related receptor alpha is involved in Alzheimer's disease-like pathology

Estrogen-related receptor alpha (ERRa) is a transcriptional factor associated with mitochondrial biogenesis and energy metabolism. However, little is known about the role of ERRa in Alzheimer's disease (AD). Here, we report that in APP/PS1 mice, an animal model of AD, ERRa protein and mRNA were decreased in a region- and age dependent manner. In HEK293 cells that stably express human full-length beta-amyloid precursor protein (APP), overexpression of ERRa inhibited the amyloidogenic processing of APP and consequently reduced A beta(1-40/1-42) level. ERRa overexpression also attenuated Tau phosphorylation at selective sites, with the concomitant reduction of glycogen synthase kinase 3 beta (GSK313) activity. Interestingly, alterations of APP processing and Tau phosphorylation induced by hydrogen peroxide were reversed by ERRa overexpression in HEK/APP cells. 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.