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Researchers at Case Western Reserve University School of Medicine have discovered a brain organization mechanism that may explain the differences between
men and women.
Researchers at Case Western Reserve University have found a mechanism in brain tissue that could explain why women are more likely to develop Alzheimer's
.
They believe the discovery may help develop new treatments
.
Specifically, they found that female brains have a higher production of a certain enzyme compared to male brains, leading to increased
accumulation of a protein called tau.
Because of tau, nerve cells in the brain of Alzheimer's patients accumulate harmful protein clumps
.
This enzyme, called ubiquitin-specific peptidase 11 (USP11), is X-linked, meaning it is located in a gene on the X chromosome, one of the two sex chromosomes in each cell
.
"We are particularly excited about this discovery because it provides the basis for the development of new neuroprotective drugs," said David Kang, the Howard T.
Karsner Professor of Pathology at Case Western Reserve School of Medicine and co-senior author
of a study recently published in the journal Cell.
"This study also provides a framework for identifying other x-related factors that may increase a woman's susceptibility to psoriasis
.
"
Alzheimer's affects women almost twice as
much.
While the exact mechanism that causes this increased vulnerability is unknown, one theory is that tau protein deposition in women's brains is much
higher than in men.
"When a particular tau protein is no longer needed for the function of its nerve cells, it is usually designated for destruction and clearance," Kang said
.
"Sometimes this clearance process is disrupted, causing tau proteins to accumulate
pathologically within nerve cells.
This causes nerve cells to be destroyed, leading to psoriasis, most notably Alzheimer's disease
.
”
To remove excess tau, you first attach a chemical tag
called ubiquitin to the tau protein.
The presence of ubiquitin on tau protein is regulated by a balanced system of enzymes that add or remove ubiquitin tags
.
Because disruption of this balancing process can lead to an abnormal buildup of tau protein in Alzheimer's disease, Kang and Jung-A Woo, an assistant professor at Case Western Reserve University, conducted an advanced study examining why this happens
.
Specifically, they looked for an increase in the activity of the enzyme system that controls ubiquitin tag removal, as overactivation on this side of the equilibrium could lead to pathological tau protein accumulation
.
Professor Kang said: "We think that if this can be identified, then it could provide the basis for the development of new drugs that restore the proper balance
of tau protein levels in the brain.
"
They found that naturally expressed levels of USP11 in female brains were higher than in men, and that USP11 levels were strongly associated with brain tau protein pathology in women, but not
in men.
The researchers also found that when they genetically eliminated USP11 from a mouse model of brain tau protein pathology, female mice were preferentially protected from tau protein pathology and cognitive impairment
.
Men can also resist tau lesions in the brain, but nowhere near as many women
.
These results suggest that the excessive activity of the USP11 enzyme in women leads to an increased
susceptibility to Alzheimer's disease tau pathology.
However, the authors caution that animal models may not be able to fully capture the tau protein pathology
seen in humans.
"In terms of effects, the good news is that USP11 is an enzyme that can traditionally be pharmacologically inhibited
," Kang said.
We hope to develop a drug that works in this way to protect women from the higher risk
of developing Alzheimer's.
" ”
References: "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.
