Researchers at Case Western have found an enzyme, more common in female brains, which appears to be responsible for driving the formation of tau protein clumps — a key Alzheimer’s biomarker.
Although it has long been known that women are more susceptible to Alzheimer’s than men – two-thirds of Americans with Alzheimer’s are women – there hasn’t been a consensus about why. Researchers from Case Western Reserve University believe that they have found a possible culprit for why women suffer from Alzheimer’s so much more often than men. They found a new link between a specific enzyme and one of the most commonly believed culprits of Alzheimer’s, the tau protein.
“We are particularly excited about this finding because it provides a basis for the development of new neuroprotective medicines,” said David Kang, the Howard T. Karsner Professor in Pathology at the Case Western Reserve School of Medicine, in a press release. “This study also sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women.”
The research findings show that female brains secrete more of an enzyme called ubiquitin-specific peptidase 11, or USP11. USP11 removes ubiquitin tags from proteins: This includes the infamous tau protein, one of the major brain suspects of Alzheimer’s. USP11 is sex-linked to the x chromosome, of which women have two, while men only have one. Since women have higher levels of USP11, they end up with more clumps of tau proteins, the study shows.
“When a particular tau protein is no longer needed for its nerve cell’s function, it is normally designated for destruction and clearance,” Kang said. “Sometimes this clearance process is disrupted, which causes tau to pathologically aggregate inside nerve cells. This leads to nerve cell destruction in conditions called tauopathies, the most well-known of which is Alzheimer’s disease.”
The study didn’t originate as a way to better understand the higher prevalence of Alzheimer’s disease in women. Rather, it began as a screen to identify enzymes that removed ubiquitin from tau proteins, as malfunctioning of the ubiquitin tagging process can lead to tau buildup.
The researchers went on to remove USP11 from female mice and found that removing the gene protected against tau accumulation and was shown to ease cognitive decline. With USP11 eliminated, the female mice were even more protected from tau pathology than male mice who underwent the same procedure.
Tau buildup doesn’t only trigger Alzheimer’s disease. It is also related to multiple system atrophy, corticobasal degeneration, frontotemporal dementia, and chronic traumatic encephalopathy, or CTE.
The study authors point out that though this may seem like cause for alarm, it is actually a positive: It could lead to more specified treatments.
“If you don’t know the cause, you can’t do anything about it,” Kang said. With a focus on a possible cause, research teams can target USP11 in further studies and drug development.
Until this research matures and leads to the next steps, women can only focus on modifiable lifestyle factors to individually decrease their risk of developing Alzheimer’s. Women (and men!) should focus on staying active, eating a balanced diet, and maintaining social connections.
Next, researchers need to determine if the way the mouse brains reacted to the experiment translates to humans. The research team is optimistic about the findings because, historically, enzymes respond well to pharmacological interventions. They believe that this breakthrough could lead to the development of drugs to protect women from their higher incidence of Alzheimer’s disease.
