RETRACTED ARTICLE: Treatment with a brain-selective prodrug of 17β-estradiol improves cognitive function in Alzheimer’s disease mice by regulating klf5-NF-κB pathway

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.

A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy

“…Thus far, DHED (Figure 3B) has been studied most extensively in preclinical animal models of E2-responsive maladies [23,36,50,51]. The unprecedented CNS selectivity of our approach in terms of prodrug bioactivation has also recently been confirmed independently from our laboratory [52,53]. We have also unambiguously shown the CNS-selective bioactivations of HEDD and αDHD to E1 and αE2, respectively [35,37].…”

“…Consequently, these animals had a higher cognitive performance, similar to those treated with the parent E2, when compared to the untreated control group. An independent follow-up study not only have confirmed these promising results, but also found that DHED treatment reduced oxidative and inflammatory stress, as well as decreased phosphorylated tau (τ) protein levels in OVX transgenic AD mouse [52]. An investigation focusing on assessing DHED’s therapeutic potential in males of the APPswe/PS1dE9 DTG-mouse AD model also revealed reduction of Aβ formation and protection against Aβ-associated cognitive impairment, as summarized in Figure 7 [51].…”

CHAS, a deconvolution tool, infers cell type-specific signatures in bulk brain histone acetylation studies of neurological and psychiatric disorders

“…Notably, THAP1 has been observed to have a binding site in the specificity protein 1 (Sp1) promoter in humans 31 , and Sp1 was reported to be enriched for binding motifs in AD hyperacetylated peaks in Marzi et al (2018). Amongst microglia-specific and oligodendrocyte-specific AD hyperacetylated peaks we observed significant enrichment of binding motifs for Krüppel-like transcription factor 5 (KLF5) (microglia: P < 1 × 10 −16 , oligodendrocytes: P < 1 × 10 −91 ), a transcription factor implicated in inflammatory responses 32 .…”

Roles of Krüppel‐like factor 5 in kidney disease

“…Moreover, sex hormones were known to influence kidney disease 62 . It was reported that androgen‐induced KLF5 expression in human breast cancer cell lines and a prodrug of 17β‐oestradiol inhibited KLF5‐NFκB inflammatory pathway in the Alzheimer's Disease mouse model 63,64 . In addition, oncogenic regulator protein SET inhibited KLF5 activation by binding to its DNA‐binding domain (DBD).…”