Microglia in the adult mouse brain have sex-specific transcriptomic signatures that remain stable even after transplantation of the cells into a brain of the opposite sex, new research published in Cell Reports reveals. These findings could help to explain sex differences in neurological disease susceptibility and outcomes.

Credit: Lara Crow/Macmillan Publishers Limited

“What prompted us to compare the microglial transcriptome of males and females was the fact that microglial activity appears to be relevant for neurodegeneration, and that several neurodegenerative diseases have a sex-related prevalence,” explains study leader Adriana Maggi. “For example, Parkinson disease is more prevalent in males than in females, whereas the opposite is true for Alzheimer disease.”

Through the use of RNA sequencing, the researchers identified 546 genes that showed differential levels of expression between microglia from male and female mice. The male microglial transcriptome showed enrichment for genes associated with inflammation, suggesting that male microglia tend to adopt a more inflammatory phenotype than their female counterparts.

The male microglial transcriptome showed enrichment for genes associated with inflammation

Phenotypic differences between male and female microglia have previously been attributed to the effects of sex hormones. However, Maggi and colleagues found that ovariectomy, which dramatically reduces the levels of circulating oestrogen, did not substantially alter the patterns of microglial gene expression in the brains of adult female mice.

The sex-specific transcriptomic signatures were maintained when microglia were transplanted into the brains of mice of the opposite sex. In addition, transplantation of female microglia into the brains of male mice mitigated the progression of cerebral ischaemia, suggesting a role for sex-specific microglial characteristics in determining the impact of brain insults.

“We would now like to know when microglia differentiate into the male and female phenotypes,” says Maggi. “We also need to understand whether this sexual differentiation has any relevance to disorders that are more prevalent in males or females, and whether sex hormones have any role in microglial ageing.”