A study in mice and human brain tissue by researchers at Case Western Reserve University has uncovered a mechanism that may explain the sex-based differences in Alzheimer’s disease, and also suggest why females are more vulnerable. The work found that compared with male brains, female brains express higher levels of an X-linked enzyme called ubiquitin-specific peptidase 11 (USP11), resulting in greater accumulation of a protein called tau. The team’s experiments also showed that genetic elimination of usp11 in a tauopathy mouse model preferentially protected females from tau pathology, and cognitive impairment.”

“This study sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women,” said David Kang, PhD, who is co-senior author of the team’s report, which is published in Cell, and titled, “X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women.” In their paper the authors concluded, “In addition to presenting novel insights for preventing human tauopathies in women, this study also sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women.”

Alzheimer’s disease affects women more than it does men, but the mechanistic basis for this increased female vulnerability to the neurodegenerative disorder has not been clear, the authors acknowledged. “Although it is well-known that women are afflicted by Alzheimer’s disease (AD) ~1.7 times more frequently than men, the mechanistic basis for this increased vulnerability has not been established.” One potential explanation is that women exhibit significantly higher tau deposition in the brain. “…positron emission tomography (PET) studies show that clinically normal women exhibit significantly higher tau deposition in the brain than men, suggesting that sexual dimorphism in tau burden could be an early foundational event for AD,” the scientists continued. “Furthermore, a recent study of post-mortem brain tissue from upwards of 1,500 age- and education-matched AD patients revealed significantly higher tau deposition in women compared to men.”

The process of eliminating excess tau begins with the addition of a chemical tag called ubiquitin to the tau protein. Because dysfunction of this process can lead to abnormal accumulation of tau, Kang and co-senior study author Jung-A.A. Woo, PhD, of Case Western Reserve University, looked for increased activity of the enzymatic systems that either add or remove the ubiquitin tag.

They found that both female mice and humans naturally express higher levels of USP11 in the brain than males, and also that USP11 levels correlated strongly with brain tau pathology in females but not in males. Moreover, when they genetically eliminated USP11 in a mouse model of brain tau pathology, females were preferentially protected from tau pathology and cognitive impairment. Males were also protected against tau pathology in the brain, but not nearly to the extent as in females.

The results suggest that excessive activity of the USP11 enzyme in females drives their increased susceptibility to tau pathology in Alzheimer’s disease. Commenting on their combined results, the team stated, “ … we show a mechanism of sex-based vulnerability to greater tau burden by virtue of physiologically higher expression of USP11 in the female brain compared with males …Overall, our unbiased identification of USP11 as a DUB driving strong female-biased effects on tauopathy in humans and mice underpins a new mechanistic basis for greater vulnerability to tauopathy in women from a preclinical stage.”

The team does further caution that mouse models of tauopathy may not fully capture the sexual dimorphism in tau pathology seen in humans. Nevertheless, they concluded, “ … inhibiting USP11-mediated tau deubiquitination may provide an effective therapeutic opportunity to protect women from increased vulnerability to AD and other tauopathies.”

“In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically,” Kang says. “Our hope is to develop a medicine that works in this way, in order to protect women from the higher risk of developing Alzheimer’s disease.”