Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Department of Neurology, Shenzhen Hospital of Peking University, Shenzhen, 518036, China.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Jul;392(7):879-886. doi: 10.1007/s00210-019-01639-w. Epub 2019 Mar 16.
10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) which is a brain-selective prodrug of 17β-estradiol has been reported to improve the cognitive function in Alzheimer's disease (AD) mice model. However, little is known about the potential mechanism for cognitive improvement. In the present study, we used AD mice to investigate the effects and mechanisms of DHED treatment. Female Tg2576 transgenic AD mice were ovariectomized and then treated by implanting Alzet osmotic minipumps containing DHED or vehicle subcutaneously for 8 weeks. Consistent with previous report, DHED treatment ameliorated cognitive function of AD mice with decreasing Aβ levels in the hippocampus. Besides, we also found DHED treatment could reduce oxidative and inflammatory stress and the level of p-tau. The mechanisms underlying the cognitive function improvement may be linked with estrogen receptor (ER)-klf5-NF-κB pathway, demonstrated by decreased expression of klf5 and the secretion of inflammatory cytokines. However, the effects of DHED treatment could be reversed when ERα was inhibited by ICI182780. Taken together, our findings uncovered a new mechanism for DHED to improve the cognitive function of AD mice and may provide a viable therapy to treat AD.
10β,17β-二羟基雌-1,4-二烯-3-酮（DHED）是 17β-雌二醇的脑选择性前药，已被报道可改善阿尔茨海默病（AD）小鼠模型的认知功能。然而，对于认知改善的潜在机制知之甚少。在本研究中，我们使用 AD 小鼠来研究 DHED 治疗的作用和机制。雌性 Tg2576 转基因 AD 小鼠接受卵巢切除术，然后通过皮下植入含有 DHED 或载体的 Alzet 渗透微型泵进行治疗，持续 8 周。与之前的报道一致，DHED 治疗改善了 AD 小鼠的认知功能，同时降低了海马体中的 Aβ 水平。此外，我们还发现 DHED 治疗可降低氧化和炎症应激以及 p-tau 的水平。认知功能改善的机制可能与雌激素受体（ER）-klf5-NF-κB 通路有关，表现为 klf5 表达降低和炎症细胞因子的分泌减少。然而，当 ERα 被 ICI182780 抑制时，DHED 治疗的效果会被逆转。总之，我们的发现揭示了 DHED 改善 AD 小鼠认知功能的新机制，并可能为治疗 AD 提供可行的治疗方法。
