Study highlights the critical role of TLR7 in sex-biased Alzheimer’s-related demyelination

Weill Cornell MedicineDec 2 2024

Inhibiting an immune signaling protein called TLR7 may help preserve the protective layer surrounding nerve fibers in the brain during both Alzheimer's disease and ordinary aging, suggests a study led by researchers at Weill Cornell Medicine.

Most nerve fibers in vertebrates are encased in sheaths made largely of a protein called myelin, which protects the fibers and greatly enhances the efficiency of their signal conduction. The destruction of myelin sheaths—demyelination—can occur in the context of brain inflammation and can lead to cognitive, movement and other neurological problems. The phenomenon is seen in multiple sclerosis (MS), Alzheimer's, Parkinson's, and other neurological conditions, as well as in ordinary aging.

Demyelination-linked disorders often show sex differences, and in the study, published Nov. 28 in Science, the researchers looked for underlying mechanisms of demyelination that might help explain these differences. Their experiments in mouse models of Alzheimer's uncovered TLR7 as a driver of inflammatory demyelination especially in males, but also showed that removing or inhibiting this immune protein can protect against demyelination in both males and females.

Our findings have potential clinical implications, and highlight the need to consider sex differences in studies of sex-biased neurological diseases such as Alzheimer's."

Dr. Li Gan, study senior author, director of the Helen and Robert Appel Alzheimer's Disease Research Institute and the Burton P. and Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute, Weill Cornell Medicine

The study's first author is Dr. Chloe Lopez-Lee, a postdoctoral research associate in the Gan Laboratory.

Nearly two-thirds of Alzheimer's patients are women, and the fact that women on average live longer than men does not fully account for this discrepancy. Women also make up nearly four-fifths of cases of MS, in which demyelination features very prominently. Parkinson's disease, on the other hand, features demyelination but predominantly affects men. The underlying mechanisms for such sex differences have been largely unknown.

In the study, the researchers showed that in older mice, females are more susceptible than males to a chemically induced form of demyelination—showing more severe demyelination and movement abnormalities—whereas young mice show milder effects with no sex difference. Using a special mouse model designed for studying contributions of sex hormones versus sex chromosomes, the team detailed gene changes in different brain cells, such as in myelin-making cells called oligodendrocytes, before, during and after demyelination. These changes were consistent with the observed demyelination differences, with sex hormones and sex chromosomes playing differential roles. The researchers observed existence of multiple sex-biased mechanisms explaining female vulnerability to demyelination in this model, including more robust uptake of myelin by male immune cells, while more myeline loss in females.

The scientists next examined demyelination in mice engineered to develop Alzheimer's-like abnormal tau-protein accumulation in brain cells, combined with the APOE4 gene variant—a major genetic risk factor for Alzheimer's. They found that male mice exhibited worse demyelination and heightened inflammatory responses, including interferon responses typically used by the body to combat infections.

"The relationships between biological sex and disease vulnerabilities are deeply nuanced—until we uncover the mechanisms underlying these relationships, we cannot fully understand such diseases," said Dr. Lopez-Lee.

The researchers ultimately traced the male-biased interferon responses to TLR7, a gene located on the X chromosome. Deleting the TLR7 gene eliminated the excess interferon response in older male mice and reduced chemically-induced demyelination and associated motor dysfunction in both older males and females. Additionally, a compound that inhibits TLR7 activity decreased demyelination and protected against tau-induced hindlimb paralysis in another mouse model with AD-linked tau protein aggregates.

These findings highlight the critical role of TLR7 in sex-biased demyelination and suggest that inhibiting TLR7 could be a promising strategy for preventing demyelination in Alzheimer's and possibly other brain disorders. The research team is now working to develop a more selective brain permeable TLR7 inhibitor for further testing, said Dr. Gan.

More broadly, researchers believe that the deeper understanding of sex differences in the disease mechanisms opens exciting new avenues for developing targeted, personalized treatments for both sexes.