Case Western Reserve University researchers have identified a mechanism in brain tissue which will explain why women are more vulnerable to Alzheimer’s disease-;a finding that they are saying could help result in recent medicines to treat the disease.

Specifically, the researchers found that the feminine brain shows higher expression of a certain enzyme in comparison with males, leading to greater accumulation of a protein called tau. The tau protein is accountable for the formation of toxic protein clumps inside brain nerve cells of Alzheimer’s disease patients.

The enzyme, generally known as ubiquitin-specific peptidase 11 (USP11), is X-linked, meaning it’s present in genes on the X chromosome, considered one of the 2 sex chromosomes in each cell.

“We’re particularly enthusiastic about this finding since it provides a basis for the event of latest neuroprotective medicines,” said David Kang, the Howard T. Karsner Professor in Pathology on the Case Western Reserve School of Medicine and co-senior writer of a study published today within the journal Cell. “This study also sets a framework for identifying other X-linked aspects that would confer increased susceptibility to tauopathy in women.”

Alzheimer’s, women and tau

Women are afflicted by Alzheimer’s disease roughly twice as continuously as men. The mechanism behind this increased vulnerability is unclear, but one potential explanation is that girls exhibit significantly higher tau deposition within the brain.

When a specific tau protein isn’t any longer needed for its nerve cell’s function, it is often designated for destruction and clearance. Sometimes this clearance process is disrupted, which causes tau to pathologically aggregate inside nerve cells. This results in nerve cell destruction in conditions called tauopathies, essentially the most well-known of which is Alzheimer’s disease.”

David Kang, the Howard T. Karsner Professor in Pathology, Case Western Reserve School of Medicine

The technique of eliminating excess tau begins with the addition of a chemical tag called 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 dysfunction of this balanced process can result in abnormal accumulation of tau in Alzheimer’s disease, Kang and co-senior study writer Jung-A Woo, assistant professor at Case Western Reserve, looked for why this might occur.

Specifically, they searched 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 on to pathological tau accumulation.

“We reasoned that if this might be identified, then it could provide a basis for the event of latest medicine that would restore the correct balance of tau levels within the brain,” Kang said.

They found that girls naturally express higher levels of USP11 within the brain than males, and in addition that USP11 levels correlate strongly with brain tau pathology in females but not in males.

Possible protection for ladies

The researchers also found that once they genetically eliminated 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 within 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. Nonetheless, the authors caution that animal models may not fully capture the tau pathology seen in humans.

“By way of implications, the excellent news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically,” Kang said. “Our hope is to develop a medication that works in this manner, with the intention to protect women from the upper risk of developing Alzheimer’s disease.”

Case Western Reserve University is considered one of the country’s leading private research institutions. Situated in Cleveland, we provide a novel combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,800 undergraduate and 6,300 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.

Source:

Case Western Reserve University

Journal reference:

Yan, Y., et al. (2022) X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women. Cell. doi.org/10.1016/j.cell.2022.09.002.