Researchers at Case Western Reserve University have identified a mechanism in brain tissue that may explain why women are more vulnerable to Alzheimer’s disease -; a discovery which they believe could contribute to the development of new drugs to treat the disease.
Specifically, the researchers found that the female brain shows higher expression of a certain enzyme compared to males, leading to greater buildup of a protein called tau. The tau protein is responsible for the formation of clumps of toxic proteins inside the brain nerve cells of patients with Alzheimer’s disease.
The enzyme, known as ubiquitin-specific peptidase 11 (USP11), is X-linked, meaning it is found in the genes of the X chromosome, one of the two sex chromosomes of each cell.
“We are particularly excited about this finding because it provides a foundation for the development of new neuroprotective drugs,” said David Kang, Howard T. Karsner Professor of Pathology at Case Western Reserve School of Medicine and co-lead author of a study. published today in the journal Cell. “This study also establishes a framework for identifying other X-linked factors that may confer increased susceptibility to tauopathy in women.”
Alzheimer, women and tau
Women are affected by Alzheimer’s disease about twice as often as men. The mechanism behind this increased vulnerability is unclear, but one potential explanation is that women have significantly higher tau deposits in the brain.
When a particular tau protein is no longer needed for its nerve cell to function, it is normally designated to be broken down and eliminated. Sometimes this clearance process is disrupted, causing the pathological aggregation of tau inside nerve cells. This leads to the destruction of nerve cells in conditions called tauopathies, the best known of which is Alzheimer’s disease.”
David Kang, Howard T. Karsner Professor of Pathology, Case Western Reserve School of Medicine
The process of removing excess tau begins with adding a chemical tag called ubiquitin to the tau protein. The presence of ubiquitin on tau is regulated by a balanced system of enzymes that add or remove the ubiquitin tag.
Since dysfunction of this balanced process can lead to abnormal accumulation of tau in Alzheimer’s disease, Kang and study co-lead author Jung-A Woo, an assistant professor at Case Western Reserve, investigated why it could happen.
Specifically, they looked for increased activity of the enzyme system controlling removal of the ubiquitin tag, since overactivation of this side of the scale could lead to pathological accumulation of tau.
“We thought that if this could be identified, then it could provide a basis for the development of a new drug that could restore the proper balance of tau levels in the brain,” Kang said.
They found that women naturally express higher levels of USP11 in the brain than men, and also that USP11 levels are strongly correlated with brain tau pathology in women but not in men.
Possible protection for women
The researchers also found that when they genetically knocked out USP11 in a mouse model of brain tau pathology, females were preferentially protected against tau pathology and cognitive impairment. Males were also protected against tau pathology in the brain, but not as much as in females.
These results suggest that excessive activity of the USP11 enzyme in women leads to their increased susceptibility to tau pathology in Alzheimer’s disease. However, the authors caution that animal models may not fully capture the tau pathology seen in humans.
“In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be pharmacologically inhibited,” Kang said. “Our hope is to develop a drug that works in this way, to protect women from the higher risk of developing Alzheimer’s disease.”
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Yan, Y. et al. (2022) X-linked ubiquitin-specific peptidase 11 increases susceptibility to tauopathy in women. Cell. doi.org/10.1016/j.cell.2022.09.002.