Alzheimer’s disease is more frequent among women than among men – specifically, they are about twice as likely to develop it – and one of the hypotheses is that this is due to the fact that this neurodegenerative pathology is associated with the aging process and women live longer. Now, the findings of a new study conducted by researchers at Case Western Reserve University (USA) could explain why the female sex is more vulnerable to developing this type of dementia.
The authors of the work observed that in the brains of women there is a greater expression of an enzyme linked to the X chromosome called ubiquitin-specific peptidase 11 (USP11) compared to men, which causes a greater accumulation of the protein tau, which in turn is the cause of the protein clumps that have been found in Alzheimer’s patients to build up.
Finding possible causes of Alzheimer’s is an advance in understanding the disease and may contribute to the development of new treatments. “This study establishes a framework to identify other factors linked to the X chromosome, which could confer greater susceptibility to tauopathy in women,” said David Kang, from Case Western Reserve University and co-senior author of the study, which has been published in the journal Cell.
Excess tau protein and development of Alzheimer’s
The process of removing excess tau starts with the addition of a chemical tag called ubiquitin to the tau protein, and how the wrong way to do this process can trigger an abnormal accumulation of tau, Kang and study co-senior author Jung- To Woo, they looked for increased activity of enzyme systems that add or remove the ubiquitin tag.
The hope of the researchers is to develop a drug that inhibits the enzyme USP11, to protect women from the increased risk of Alzheimer’s.
They found that both female and female mice naturally express higher levels of USP11 in the brain than males, and also that USP11 levels correlate strongly with tau brain pathology in females, but not in males. They further found that by knocking out USP11 in a mouse model of tau brain pathology, females were preferentially protected from tau pathology and cognitive impairment, since, although males were also protected against tau pathology in the brain, they were not to the same extent as females.
The researchers were surprised to find that USP11 was found on X chromosomes – of which women have two – even in women without dementia. “Normally, one of the X chromosomes is more or less inactivated in women… but there are between 10 and 20% of genes on the X chromosome that can escape this inactivation,” explains Kang, adding: “USP11 is be one of them.”
The study results suggest that excess USP11 enzyme activity in women increases their susceptibility to tau pathology in Alzheimer’s disease. “We already knew that women were more affected by Alzheimer’s than men,” said Kang. “We need to know what the cause is. If you don’t know the cause, you can’t do anything about it. This study… is actually identifying a cause. Now we have the opportunity to do something about it.”
“In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically,” Kang said. “Our hope is to develop a drug that works in this way, to protect women from the increased risk of developing Alzheimer’s disease.”
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