Why Are Women More Susceptible to Alzheimer’s? Scientists May Finally Have an Answer

Senior Woman Alzheimers Disease Concept

Women are about twice as likely to develop Alzheimer’s disease as men.

Researchers from the Case Western Reserve University School of Medicine have discovered a brain tissue mechanism that might account for the disparity between men and women.

Researchers from Case Western Reserve University have discovered a mechanism in brain tissue that may explain why women are more susceptible to Alzheimer’s disease. They believe that this discovery may help develop new treatments for the disease.

Specifically, they discovered that the female brain displays higher production of a certain enzyme in comparison to the male brain, leading to increased accumulation of a protein known as tau. Alzheimer’s disease sufferers’ brain nerve cells accumulate harmful protein clumps because of the tau protein.

The enzyme, called ubiquitin-specific peptidase 11 (USP11), is X-linked, which means it is located in genes on the X chromosome, one of the two sex chromosomes in each cell.

“We are particularly excited about this finding because it provides a basis for the development of new neuroprotective medicines,” said David Kang, the Howard T. Karsner Professor in Pathology at the Case Western Reserve School of Medicine and co-senior author of a study published recently published in the journal Cell. “This study also sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women.”

Alzheimer’s, women and tau

Alzheimer’s disease affects women nearly twice as often as males. Although the exact mechanism causing this increased vulnerability is unknown, one theory is that women have considerably higher tau deposition in their brains than males do.

“When a particular tau protein is no longer needed for its nerve cell’s function, it is normally designated for destruction and clearance,” Kang said. “Sometimes this clearance process is disrupted, which causes tau to pathologically aggregate inside nerve cells. This leads to nerve cell destruction in conditions called tauopathies, the most well-known of which is Alzheimer’s disease.”

The removal of excess tau starts with the attachment of a chemical tag known as ubiquitin to the tau protein. The presence of ubiquitin on tau is regulated by a balanced system of enzymes that either add or remove the ubiquitin tag.

Because disruptions in this balanced process might result in aberrant tau buildup in Alzheimer’s disease, Kang and co-senior study author Jung-A Woo, an assistant professor at Case Western Reserve University, investigated why this can occur.

Specifically, they looked for increased activity of the enzymatic system controlling the removal of the ubiquitin tag, because over-activation of this side of the balance could lead to pathological tau accumulation.

“We reasoned that if this could be identified, then it could provide a basis for the development of new medicine 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 males, and also that USP11 levels correlate strongly with brain tau pathology in females but not in males.

Possible protection for women

The researchers also found that 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.

These results suggest that excessive activity of the USP11 enzyme in females drives 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 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.”

Reference: “X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women” by Yan Yan, Xinming Wang, Dale Chaput, Min-Kyoo Shin, Yeojung Koh, Li Gan, Andrew A. Pieper, Jung-A.A. Woo and David E. Kang, 4 October 2022, Cell.
DOI: 10.1016/j.cell.2022.09.002

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