Demyelination is associated with aging and age-related neurodegenerative disorders, including Alzheimer’s disease, and has shown sex differences in prevalence. In Science, Lopez-Lee et al. find that the X-linked gene Trl7 regulates male-biased type I IFN responses in a mouse model of aging-related demyelination. In aging mice treated with a demyelinating agent, females developed more severe disease. Using the Four Core Genotype (FCG) mouse model, which enables independent assessment of gonadal and sex chromosomal effects, authors found that ovaries after demyelination were associated with increased cytokine levels and worsened disease, whereas sex chromosomes had a bigger role in controlling microglial activation, with higher activation associated with XY chromosomes. FCG mice were bred onto an APOE4 background and then crossed with a tauopathy model. XY chromosomes were associated with higher levels of disease-associated microglia and increased NF-κB, STING and IFN signaling, but myelin loss only occurred when XY chromosomes and testes were present. During demyelination in aging mice, Tlr7 was downregulated in microglia when XX chromosomes and ovaries were present and knockout of TLR7 reduced male-biased IFN responses and protected against demyelination. In the tauopathy model, inhibiting TLR7 reduced myelin loss and protected against hindlimb paralysis in males. TLR7 has an important role in driving the male-biased IFN response and demyelination-induced deficits in both sexes.

Original reference: Science 386, eadk7844 (2024)