Scientists at UCLA Health have identified a gene on the X chromosome that fuels inflammation in the female brain, providing a fresh explanation for why women are more frequently affected by neurological conditions such as Alzheimer’s disease and multiple sclerosis. The gene, called Kdm6a, was shown to heighten immune activity within microglia – the brain’s specialised immune cells. Because females possess two X chromosomes rather than one, they receive a more potent dose of this inflammatory signal, which becomes particularly relevant in diseases characterised by age-related neurodegeneration.
The research, published in Science Translational Medicine, demonstrated that disabling Kdm6a in a mouse model of multiple sclerosis significantly reduced both disease severity and the damage visible in brain tissue. When the gene was genetically removed, inflammatory molecules within microglia shifted from an activated state back to a more protective, resting state. The team also used the diabetes drug metformin to reduce production of the protein linked to Kdm6a, producing similar benefits. Notably, these interventions had a meaningful impact only in female mice, suggesting that the double X chromosome dosage plays a central role and that women and men may respond differently to treatments that target this pathway.
According to study lead Dr Rhonda Voskuhl, the findings help clarify why neurological disorders disproportionately affect women and why many experience cognitive “brain fog” during menopause. She explained that women’s immune systems have evolved to strike a balance: X-linked inflammatory activity provides an advantage in combating infections during childbearing years, while oestrogen acts as a natural brake that protects the brain from inflammation-induced damage. When oestrogen levels drop during menopause, the protective balance is disrupted, allowing inflammation to exert more harmful, neurodegenerative effects.
The research points toward possible treatment strategies that restore this equilibrium. Voskuhl suggests that therapies targeting brain-specific oestrogen pathways, alongside drugs that moderate Kdm6a activity, could help shield the ageing female brain from the excess inflammation driven by sex-chromosome biology. By illuminating how genetic and hormonal factors interact, the study opens the door to more personalised approaches to neurological health, recognising that understanding women’s risk means paying close attention not only to hormones but also to the chromosomes that shape immune activity throughout life.
More information: Yuichiro Itoh et al, Deletion of the X-chromosomal gene Kdm6a in microglia of female mice ameliorates neuroinflammation and restores translatome profiles, Science Translational Medicine. DOI: 10.1126/scitranslmed.adq3401
Journal information: Science Translational Medicine Provided by University of California – Los Angeles Health Sciences
