A new study by researchers from Case Western Reserve University may help explain the sex-based difference in the incidence rate of Alzheimer’s disease (AD) that makes women more vulnerable to the disease. The research, published today in the journal Cell, shows that higher expression of the X-linked enzyme ubiquitin-specific peptidase 11 (USP11) in females results in greater accumulation of the tau protein known to be a key factor in Alzheimer’s development.
The incidence rate of AD is about twice as high in women as it is in men and, to date, the reasons for this difference have not been clear. A possible explanation, and one highlighted by the Case Western investigators, is that women exhibit much higher levels of tau deposition in the brain.
“This study sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women,” noted co-senior study author David Kang of Case Western.
Earlier research has shown that eliminating excess tau is initiated by the addition of a chemical tag called ubiquitin to the tau protein. The dysfunction of this process can lead to higher levels of tau, which prompted Kang and co-senior study author Jung-A.A. Woo to look study the enzymatic systems that either add or remove the ubiquitin tag.
The duo found that both female mice and humans naturally express higher levels of USP11 in the brain than males, and also that USP11 levels correlate strongly with brain tau pathology in females but not in males. The researchers then genetically eliminate USP11 in a mouse model of brain tau pathology and discovered that females were preferentially protected from tau pathology and cognitive impairment as a result. The data showed that males, too, were protected against tau pathology in the brain, but conferred much higher protection for females.
While the study results suggest that excessive activity of the USP11 enzyme in females may be a driver of increased AD susceptibility, the researchers warn that mouse models of tauopathy may not fully capture human sexual dimorphism in humans.
“In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically,” Kang said. “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.”
