Evidence from mice and human brain tissue suggests a process that may explain the gender disparities in Alzheimer’s disease, including why females are more susceptible.

According to a study published in the journal Cell today, female brains have higher production of the X-linked enzyme ubiquitin-specific peptidase 11 (USP11) than male brains, leading to increased buildup of the tau protein.

“This study sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women,” adds co-senior study author David Kang of Case Western Reserve University.

Alzheimer’s disease affects women nearly twice as commonly as males. The mechanism underlying this increased vulnerability is unclear. One possible explanation is that women have much more tau in their brains.

The removal of excess tau begins with the attachment of a chemical tag known as ubiquitin to the tau protein. Kang and co-senior study author Jung-A Woo of Case Western Reserve University investigated for increased activity of the enzyme systems that either add or remove the ubiquitin tag since malfunction of this process might result in aberrant buildup of tau.

They discovered that female mice and humans naturally express more USP11 than males do in the brain, and that in females but not in males, USP11 levels substantially correspond with brain tau disease.

In addition, when USP11 was genetically deleted in a mouse model of brain tau pathology, females were protected against tau pathology and cognitive impairment. While males were similarly protected from brain disease caused by tau, this protection was not as strong as it was in females.

The findings imply that females’ higher sensitivity to tau pathology in Alzheimer’s disease is caused by their overactive USP11 enzyme. The sexual dimorphism in tau disease seen in humans may not be completely reflected in mice models of tauopathy, the authors warn.

The fact that USP11 is an enzyme and that enzymes can typically be suppressed pharmacologically is good news in terms of implications, according to Kang. 

“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.”

Source: 10.1016/j.cell.2022.09.002

Image Credit: Getty

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