Cell: Why are women more susceptible to Alzheimer's disease? The risk of disease in humans may be closely related to the X chromosome!

Scientists from Case Western Reserve University and other institutions have shown that women have higher levels of X-linked enzymes called ubiquitin-specific peptidase 11 than men, which may lead to higher
accumulation of tau protein in the brain.

Studies of mouse and human brain tissue suggest that there may be a special mechanism that explains sex-based differences in Alzheimer's disease, including why women are more susceptible to Alzheimer's disease
。 Recently, in a study published in the international journal Cell entitled "X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women", scientists from Case Western Reserve University and other institutions have shown that compared with men, the female brain is called ubiquitin-specific peptidase 11 (USP11, ubiquitin-specific peptidase 11) has higher levels of X-linked enzymes, which may lead to higher
accumulation of tau protein in the brain.

In this study, the researchers established a framework to identify other X-linked factors
that increase a woman's susceptibility to tauopathy.
Researchers say women develop Alzheimer's disease about twice as often as men, and the mechanism behind this increased susceptibility is unclear to researchers, and one potential explanation is that women exhibit high levels of tau protein accumulation
in their brains.

Why are women more susceptible to Alzheimer's disease? Human risk may be closely related
to the X chromosome.

Image source: Cell (2022).
DOI:10.
1016/j.
cell.
2022.
09.
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The process of eliminating excess tau protein begins with the addition of a chemical tag called ubiquitin to tau protein, and because this process is abnormal in function leading to abnormal accumulation of tau protein, researchers Kang et al.
wanted to find out whether increasing or removing ubiquitination tags could increase the activity of
this enzyme system 。 The researchers found that female mice and humans naturally express high levels of USP11 in the brain, and USP11 levels are also strongly correlated with tau lesions in female (not male) brains, in addition, when the researchers genetically removed USP11 from mouse models of brain tau lesions, female animals were preferentially protected from tau lesions and cognitive impairment of the brain; Males are also protected against tau lesions in the brain, but hardly to the extent of
females.

The results suggest that the excessive activity of the USP11 enzyme in females drives their susceptibility to Alzheimer's tau lesions, but the researchers caution that mouse models of tau proteinopathy may not fully reflect sexual dimorphism
in the pathological manifestations of tau in humans 。 In terms of impact, the good news is that USP11 is an enzyme that has traditionally been pharmacologically inhibited, and we hope to develop a drug that works as soon as possible to protect women from high-risk Alzheimer's disease
, Kang said.

Taken together, the results suggest that inhibition of USP11-mediated deubiquitination of tau may provide an effective therapeutic opportunity to protect women from an increased
risk of Alzheimer's disease and other tau proteinopathies.
(Bio Valley Bioon.
com)

Original source:

Yan Yan，Xinming Wang，Dale Chaput, et al.
 X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women, Cell (2022).
DOI: 10.
1016/j.
cell.
2022.
09.
002