Researchers at UCLA Health have pinpointed the gene on the X chromosome that drives higher levels of brain inflammation in women, illuminating why they are more susceptible to neurological disorders like Alzheimer’s disease and multiple sclerosis. This discovery opens up promising treatment possibilities.
Scientists at UCLA Health have identified a crucial gene on the X chromosome that triggers heightened brain inflammation in women, potentially explaining why they are more vulnerable to neurological disorders such as Alzheimer’s disease and multiple sclerosis.
Published in the journal Science Translational Medicine, the study focuses on the gene Kdm6a and its role in inflaming microglia, the immune cells located in the brain.
The researchers used a mouse model to demonstrate that females, possessing two X chromosomes, experience a “double dose” of inflammation, amplifying the risk for these conditions.
“It has long been known that there are sex differences in the brain. These can impact both health and neurological diseases,” lead author Rhonda Voskuhl, the director of the Multiple Sclerosis Program at UCLA Health and lead neurologist for the UCLA Comprehensive Menopause Program, said in a news release. “Multiple sclerosis and Alzheimer’s disease each affect women more often than men, about two to three times as often. Also, two-thirds of healthy women have ‘brain fog’ during menopause. These new findings explain why and point to a new treatment to target this.”
When first author Yuichiro Itoh, a member of the Voskuhl lab, genetically deactivated the Kdm6a gene in brain cells, the inflammatory molecules shifted to a resting state. The team’s pharmacologic approach using metformin, a common diabetes medication now being investigated for its anti-aging potential, corroborated these findings. The results were substantial in female mice but had minimal impact on males.
“This is consistent with there being ‘more to block’ in females due to having two copies of the X-linked gene,” added Voskuhl, who is also a professor of neurology at UCLA Health. “It’s also why females are more likely to get MS and AD than males. This has implications for the clinic. Women may respond differently to metformin treatment than men.”
The implications extend beyond metabolic treatments. Voskuhl connected these findings to menopausal brain fog, shedding light on how hormonal changes exacerbate inflammation.
“Sex chromosomes and sex hormones achieve a balance through evolution,” she said. “There is a selection bias to do so. Females have a balance between X chromosome-driven inflammation that can be good to fight infections at child-bearing ages. This is held in check by estrogen, which is anti-inflammatory and neuroprotective. As women age, menopause causes loss of estrogen, unleashing the proinflammatory and neurodegenerative effects of this X chromosome the brain immune cell.”
Source: UCLA Health