MicroRNA-138 promotes tau phosphorylation by targeting retinoic acid receptor alpha.

Alzheimer's disease (AD) is a progressive neurodegenerative dementia characterized by Aβ deposition and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Emerging evidence shows that microRNAs (miRNAs) contribute to the pathogenesis of AD. Herein, we investigated the role of miR-138, a brain enriched miRNA, which is increased in AD patients. We found that miR-138 is increased in AD models, including N2a/APP and HEK293/tau cell lines. Overexpression of miR-138 activates glycogen synthase kinase-3β (GSK-3β), and increases tau phosphorylation in HEK293/tau cells. Furthermore, we confirm that retinoic acid receptor alpha (RARA) is a direct target of miR-138, and supplement of RARA substantially suppresses GSK-3β activity, and reduces tau phosphorylation induced by miR-138. In conclusion, our data suggest that miR-138 promotes tau phosphorylation by targeting the RARA/GSK-3β pathway.