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iNature
Alzheimer's disease (AD), commonly known as Alzheimer's disease, accounts for about 60-70% of all cases, is a clinical syndrome characterized by progressive deterioration of memory function and cognitive function, mostly in old age
.
It is well known that women develop AD 1.
7 times more often than men, but the mechanism of this increased chance remains unclear
.
Tau is a class of proteins that stabilize microtubules in neurons, but it is also a multifunctional protein that plays a key role
in certain neurodegenerative diseases, such as AD.
Although the burden of tau protein is significantly higher in women compared to men, this underlying mechanism has not been explained
.
On October 4, 2022, David E.
Kang and Jung-A.
A.
Woo of Case Western Reserve University School of Medicine published an online article in Cell magazine titled "X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women.
" ".
This study demonstrated through in vitro and in vivo models and human AD brain tissue that X-associated ubiquitin specific peptidase 11 (USP11) enhances pathological tau protein aggregation
by mediating the deubiquitination of tau protein lysine (Lysine, Lys)-281.
This study provides new insights
into the prevention of TAU disease in humans.
In addition, on March 2, 2022, Ye Keqiang (former tenured professor at Emory University) from the School of Life and Health of Shenzhen University of Science and Technology, Chinese Academy of Sciences, and Mone Zaidi of Icahn School of Medicine at Mount Sinai in Yosan published a paper entitled "FSH blockade improves cognition in mice with" online in Nature Alzheimer's disease", which shows that follicle-stimulating-hormone (FSH) acts directly on hippocampal and cortical neurons to accelerate the deposition of amyloid-β and Tau and impair cognition in mice exhibiting Alzheimer's disease characteristics (click to read).
While it is known that women develop Alzheimer's (AD) more frequently than men, the mechanistic basis for this increased vulnerability has not been established
.
The researchers reasoned that this may have something to do with
the fact that women bear a greater burden of tau than men.
For example, positron emission tomography (PET) studies have shown that tau protein deposition is significantly higher in the brain in clinically normal women than in men, suggesting that sexuality of tau protein loading may be an early underlying event
of AD.
In addition, a recent study of postmortem brain tissue of more than 1500 age- and educationally matched AD patients found significantly higher tau protein deposition in women than in men
.
Tau protein aggregation and clearance is controlled by a variety of post-translational modifications, including phosphorylation, methylation, acetylation, and ubiquitination
.
Notably, ubiquitination is the final modification
that controls tau protein clearance through the ubiquitin-proteasome system and the autophagy-lysosomal pathway.
Although tau protein ubiquitination is associated with C-terminus of Hsc70-interacting protein (CHIP), tumor necrosis factor receptor-associated factor 6 (TRAF6), and membrane-associated RING-CH7 ( membrane-associated RING-CH7, MARCH7) is associated with increased tau protein clearance, but little is known
about the role of deubiquitinases (DUBs) in the brain to remove tau protein ubiquitin.
The human genome encodes about 100 DUBs, about 50% of which are ubiquitin-specific peptidases (USPs).
More than 20 of them are expressed in the central nervous system
.
To investigate their role in tau protein regulation, the researchers screened 22 CNS DUBs for functional small interfering RNA (siRNA) and identified positive regulators of two tau proteins: USP13 and USP11
.
Because USP11 is located on the X chromosome and is involved in female biology, the researchers speculate that it may contribute to a woman's
unique susceptibility to tau's disease.
In this study, the researchers presented in vitro and in vivo evidence, including in human AD brain tissue, that an increase in endogenous USP11 levels in women relative to males led to increased deubiquitination of tau protein at lysine (K) 281, and that the removal of ubiquitin provided a pathway
for tau acetylation of lysine 281 and 274 。 USP11 escaped complete inactivation of the X chromosome, and both female mice and human females showed higher levels
of USP11 than males.
In a mouse model of tau disease, knockout USP11 preferentially protects females from acetylated tau protein accumulation, tau protein pathology, and cognitive impairment
.
In women, USP11 levels are also strongly associated with tau protein pathology, but not
in men.
Overall, this study shows:
- X-related USP11 enhances acetylation and aggregation by deubiquitinating tau protein;
- USP11 escapes X inactivation, resulting in higher expression in women than in men;
- In women, USP11 levels are strongly associated with tau brain pathology, but not in men;
Knockout USP11 can protect women from tau pathology and cognitive impairment The study identified USP11 as DUB with a strong female bias effect on human and mouse tau proteinopathy, which provides a new mechanistic basis
for women to be more likely to develop tau proteinopathy from the preclinical stage.
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