[P1-3-48] Sex hormone testosterone inhibits NF-κB inflammatory pathway in microglia
キーワード：Testosterone、Microglia、Fatty acid synthase
Sex differences are evident in Alzheimer's disease (AD), with women having a higher probability and severity than men, suggesting a potential role of sex hormones in this disparity. Testosterone has been reported to regulate cognitive and memory functions in the brain, and there is a clear association between low serum testosterone levels and increased AD risk. However, the specific mechanisms underlying the relationship between testosterone and AD risk remain unclear. Recent studies have shown that microglia, the primary innate immune cells in the brain, play a crucial role in the development of AD. Thus, sex differences in microglial function may contribute to the sex-specific pathogenesis of AD. In this study, we focused on the effect of testosterone on the NF-kB inflammatory signaling pathway in a mouse microglial cell line MG6 following stimulation with lipopolysaccharide (LPS). We observed that testosterone inhibits the expression of fatty acid synthase (FASN), which in turn suppresses NF-kB/p65 phosphorylation. Consistently, the inhibition of fatty acid synthesis by a FASN inhibitor C75 suppressed the phosphorylation of p65, indicating that testosterone regulates the NF-kB inflammatory signaling pathway by regulating de novo fatty acid synthesis. Fasn expression was lower in hippocampal microglia isolated from male mice than in female mice. Microarray analyses revealed that miRNAs enriched in male microglia showed enrichment in fatty acid biosynthesis and metabolism pathways. These results suggest that the regulation of fatty acid synthesis by testosterone contributes to the suppression of inflammatory responses in male microglia, serving as a key factor in the sexually differential characteristics of microglia under inflammatory conditions.