Abstract
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.
Highlights
L Abstract C 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
Given that estrogen could degrade klf5 in estrogen receptor (ER)-positive breast cancer cells and klf5 could regulate inflammation through NF-κB pathway, we examined the expression in LE expressions were normalized to β-actin and quantified relative to that of the control AD mice. (n = 6–9/group) ANOVA, *p < 0.05 vs control or vehicle or DHED+ICI182780
IC Discussion T It has been reported that estrogen treatment has the potential R for the treatment of mouse model of AD, especially DHED
Summary
Treatment with a brain-selective prodrug of 17β-estradiol improves cognitive function in Alzheimer’s disease mice by regulating klf5-NF-κB pathway. L Abstract C 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. We used AD mice to investigate the effects and mechanisms of DHED treatment. Consistent with previous report, DHED treatment ameliorated cognitive function of AD mice with decreasing Aβ levels in the hippocampus. The mechanisms underlying the cognitive function improvement may be linked with estrogen receptor (ER)-klf5-NF-κB pathway, demonstrated by decreased expression of klf and the secretion of inflammatory. High glucose could induce KLF5 nitration and could activate the expression of inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin1β (IL-1β) in vascular smooth muscle cells (VSMCs), while 17β-estradiol could inhibit high glucose-mediated effects in VSMCs (Zhang et al 2017).
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call