MiR-15b-5p transcription mediated by CREB1 protects against inflammation and apoptosis in Parkinson disease models by inhibiting AXIN2 and activating Wnt/β-catenin.

Abstract

Parkinson disease (PD) is a major neurodegenerative disease that greatly undermines people's health and for which effective therapeutic strategies are currently limited. This study dissected the effects of expression changes of AXIN2, a modulator of the Wnt/beta-catenin signaling pathway, the transcription factor CREB1, and of the microRNA miR-15b-5p on apoptosis and the inflammatory response in a PD mouse model in vivo and in a cellular PD model in vitro. The analyses demonstrated low CREB1 and miR-15b-5p expression and high AXIN2 expression in both models. miR-15b-5p overexpression or AXIN2 knockdown alleviated the inflammatory response indicated by decreased levels of TNF-α, IL-6, and IL-1β and apoptosis indicated by decreased levels of cleaved caspase-3 and Bax and elevated Bcl-2. Protection by miR-15b-5p upregulation was counteracted by the simultaneous overexpression of AXIN2. miR-15b-5p targeted AXIN2. CREB1 promoted miR-15b-5p expression, which activated the Wnt/β-catenin pathway by inhibiting AXIN2. Collectively, the data indicate that transcriptional expression of miR-15b-5p can be promoted by CREB1 to inhibit AXIN2 and activate Wnt/β-catenin, thereby reducing the inflammatory response and apoptosis in these PD models. These data suggest the CREB1/miR-15b-5p/AXIN2 axis is a potential therapeutic target in PD patients.