MicroRNA-23b attenuates tau pathology and inhibits oxidative stress by targeting GnT-III in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease, the main pathological features include deposition of neurofibrillary tangles composed of the abnormally hyperphosphorylated tau protein and plaques deposition composed of β-amyloid (Aβ) peptide. MicroRNAs and aberrant glycosylation both play key roles in a variety of diseases, especially AD. Our previous study showed that N-acetylglucosaminyltransferase III (GnT-III) was expressed strongly in AD model mice. GnT-III is a glycosyltransferase responsible for synthesizing a bisecting N-acetylglucosamine residue. Here, we report the potential therapeutic effects of microRNA-23b (miR-23b) against AD by targeting GnT-III. In this study, the role of miR-23b in GnT-III-mediated amelioration of AD-related symptoms and pathologies, and mechanisms were investigated. We used Aβ_1-42-induced mouse and PC12 cell models to evaluate the effects of miR-23b on cognitive impairment, neurotoxicity, tau, and amyloid pathology. Bioinformatics analysis showed that GnT-III may be targeted by miR-23b, and it was verified by dual-luciferase reporter gene assays. Furthermore, a mechanistic study showed that activation of the Akt/GSK-3β signaling pathway can contribute to tau-lesion inhibition by miR-23b, and miR-23b can also restrain oxidative stress by altering Aβ-precursor protein processing. Taken together, we conclude that overexpression of miR-23b can interrupt the pathogenesis of AD.

Keywords: APP; Alzheimer’s disease; MicroRNA-23b; N-acetylglucosaminyltransferase III; Oxidative stress; Tau.