October 25, 2022

Potential contributor to sex differences in Alzheimer’s risk

At a Glance

  • Researchers found how an enzyme called USP11 contributes to the buildup of tau tangles in the brain, a hallmark of Alzheimer’s disease.
  • In mice, blocking this enzyme protected against loss of memory and learning.
  • USP11 is far more abundant in women than men, and the results suggest it plays a role in the higher risk of Alzheimer’s among women.
Senior man and woman holding hands and leaning close to each other The study’s findings may help explain why women have a higher risk of developing Alzheimer’s disease. LightField Studios / Shutterstock

Alzheimer’s disease, which can destroy the ability to think, learn, and remember, is more common in women than men. The reasons for this disparity between the sexes are not well understood.

Women are known to have greater levels of tau protein abnormally build up in brain cells over their lives. The structures that form, called tau tangles, are one of the hallmarks of Alzheimer’s disease.

An NIH-funded research team led by Drs. David Kang and Jung-A “Alexa” Woo from Case Western Reserve University has been searching for molecules in the brain that may be driving tau accumulation in women. Their new study was published on October 13, 2022, in Cell.

Tau is needed for the normal functioning of brain cells called neurons. In healthy neurons, old, damaged, or unneeded tau molecules are tagged for recycling and removal by the brain’s waste system. Enzymes called ubiquitinases place these tags. Other enzymes called deubiquitinases can remove these tags. Together, they help regulate when molecules are disposed of.

The team screened for deubiquitinases in the brain that might be stopping tau recycling. When they blocked one such enzyme called USP11, levels of tau in cells, including the type that can tangle, dropped substantially.

Further experiments confirmed that USP11 was removing the recycling tags from tau. When this happened, other enzymes added different molecular tags called acetyl groups, which are known to trigger the tangling process. The researchers found almost 10 times as much USP11 in tissue samples taken from people with Alzheimer’s disease as in those taken from people without the condition.

The gene that encodes USP11 is found on the X chromosome. Women have two copies of this chromosome, while men only have one. While one X chromosome is usually inactive in cells, some genes, such as the one for USP11, stay active on both. The researchers found that high USP11 levels were more strongly associated with tau tangles in samples taken from female brains than from male brains.

The team saw similar results in samples taken from the brains of female and male mice. Mice engineered to lack the gene that produces the mouse version of USP11, called usp11, had substantially less tau tagged with acetyl groups for it to tangle. As seen in the human samples, this improvement was far more substantial in female mice.

Compared to female mice that could produce usp11, those engineered to lack usp11 had far better performance on tests of memory and learning as they aged. Male mice that lacked usp11 only showed a small improvement. These findings show how USP11 can affect the development of Alzheimer’s disease differently in men and women.

“In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited [with drugs],” Kang says. “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.”

—by Sharon Reynolds

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References: X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women. Yan Y, Wang X, Chaput D, Shin MK, Koh Y, Gan L, Pieper AA, Woo JA, Kang DE. Cell. 2022 Oct 13;185(21):3913-3930.e19. doi: 10.1016/j.cell.2022.09.002. Epub 2022 Oct 4. PMID: 36198316.

Funding: NIH’s National Institute on Aging (NIA) and National Institute of Neurological Disorders and Stroke (NINDS); United States Department of Veterans Affairs; Howard T. Karsner Professorship in Pathology; Rebecca E. Barchas MD Professorship in Translational Psychiatry; American Heart Institute–Allen Initiative in Brain Health and Cognitive Impairment; Elizabeth Ring Mather & William Gwinn Mather Fund; S. Livingston Samuel Mather Trust; G.R. Lincoln Family Foundation; Wick Foundation; Leonard Krieger Fund of the Cleveland Foundation; Gordon and Evie Safran.