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 (Aβ_25–35) treated BV-2 cells was evaluated in this study. Our results demonstrated that Aβ_25–35 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.

小胶质细胞表型极化，分为促炎性“ M1”表型和抗炎性“ M2”表型，在阿尔茨海默病（AD）的发病机理中起着至关重要的作用。从M1到M2表型促进小胶质细胞极化可减轻AD相关的病理损伤，而小胶质细胞表型的调节剂已成为治疗AD的有前途的治疗方法。先前的少量证据表明，DHCR24（3-β-羟基类固醇-Δ-24-还原酶），也称为seladin-1（选择性阿尔茨海默病指示剂-1），具有潜在的抗炎作用，但是，DHCR24与小胶质细胞之间存在联系极化从未被报道过。因此，DHCR24的在β-淀粉样25-35小胶质细胞极化作用（Aβ _25-35在本研究中评估了处理过的BV-2细胞。我们的研究结果表明，Aβ _25-35加重炎症反应，促进了小神经胶质细胞表现型的从M2到M1在BV-2细胞的过渡，通过上调M1标记（I-NOS，IL-1β和TNF-α）和下调M2标记（精氨酸酶-1，IL-4和TGF-β）。慢病毒转染过表达DHCR24可以显着逆转这些作用，同时通过增加P-Akt和P-GSK3β的蛋白表达来激活Akt /GSK3β信号通路。此外，当与Akt抑制剂MK2206共同治疗时，DHCR24的作用明显被逆转。这项研究展示了DHCR24在与AD相关的炎性损伤中的神经保护功能，并为将来的AD提供了新的治疗靶标。