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Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia
Haolin Zheng1, Akiko Mizokami2, Sergio Romera-Giner3
1Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
Background:
Significant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.
Methods:
Microglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.
Results:
Sex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.
Conclusions:
These findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.
Insights
Testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially impacting Alzheimer's disease (AD) risk. This study reveals testosterone's role in microglial gene expression and inflammatory pathways relevant to AD pathogenesis.
Area of Science:
- Neuroimmunology
- Endocrinology
- Molecular Biology
Background:
- Significant sex differences exist in Alzheimer's disease (AD) prevalence.
- Testosterone influences cognitive function, and low levels correlate with increased AD risk.
- Microglia, the brain's immune cells, are crucial in AD development.
Purpose of the Study:
- Investigate sex differences in microglial function.
- Explore testosterone's role in miRNA-mediated microglial gene expression.
- Elucidate mechanisms linking testosterone, microglia, and AD.
Main Methods:
- Isolated microglia from male and female mice for miRNA microarray analysis.
- Utilized mouse microglial cell line (MG6) for in vitro testosterone treatment.
- Assessed miRNA, gene, and protein expression, including inflammatory markers post-LPS stimulation.
Main Results:
- Observed sex-dependent differences in miRNA expression, with males showing greater changes.
- Testosterone upregulated male-enriched miRNAs targeting fatty acid synthesis genes in MG6 cells.
- Testosterone inhibited fatty acid synthase (FASN) expression, reducing inflammation (NF-κB/p65 phosphorylation and TNF-α).
Conclusions:
- Testosterone modulates inflammation in male microglia via fatty acid synthesis regulation.
- Findings suggest a mechanism contributing to sex differences in AD pathogenesis.
- Highlights the role of testosterone in microglial immune responses relevant to AD.
