DHCR24 overexpression modulates microglia polarization and inflammatory response via Akt/GSK3β signaling in Aβ25-35 treated BV-2 cells.

Microglial phenotypic polarization, divided into pro-inflammatory "M1" phenotype and anti-inflammatory "M2" phenotype, played a crucial role in the pathogenesis of Alzheimer's disease (AD). Facilitating microglial polarization from M1 to M2 phenotype was shown to alleviate AD-associate pathologic damage, and modulator of the microglial phenotype has become a promising therapeutic approach for the treatment of AD. Previous little evidence showed that DHCR24 (3-β-hydroxysteroid-Δ-24-reductase), also known as seladin-1 (selective Alzheimer's disease indicator-1), exerted potential anti-inflammatory property, however, the link between DHCR24 and microglial polarization has never been reported. Thus, the role of DHCR24 in microglial polarization in amyloid-beta 25-35 (Aβ25-35) treated BV-2 cells was evaluated in this study. Our results demonstrated that Aβ25-35 aggravated inflammatory response and facilitated the transition of microglia phenotype from M2 to M1 in BV-2 cells, by upregulating M1 marker (i-NOS, IL-1β and TNF-α) and downregulating M2 marker (arginase-1, IL-4 and TGF-β). DHCR24 overexpression by lentivirus transfection could significantly reverse these effects, meanwhile, activated Akt/GSK3β signaling pathway via increasing the protein expression of P-Akt and P-GSK3β. Furthermore, when co-treated with Akt inhibitor MK2206, the effect of DHCR24 was obviously reversed. The study exhibited the neuroprotective function of DHCR24 in AD-related inflammatory injury and provided a novel therapeutic target for AD in the future.