Senolytic treatment improves cognition in female Alzheimer’s mice
Research shows differing effects from treatment for male, female models
One of the many confounding questions about Alzheimer’s disease is why women are at greater risk.
Of the approximately 7 million people diagnosed with Alzheimer’s in the United States, nearly two-thirds are women. There are several theories as to why, including that women live longer than men, societal factors, biological factors and more. But the question is far from answered.
That gender imbalance may be a significant factor when developing new treatments as well.
A recent study from the Hascup Lab at the Smith Alzheimer’s Center at SIU Medicine showed senolytic treatments showed different responses from male and female mouse models. Female mouse models showed significant improvements in cognition, metabolism and fat accumulation compared to males with one drug compound in particular.
The current findings, published in Geroscience, suggest a person’s sex can influence the effectiveness of early intervention when treating Alzheimer’s disease, much like it affects their risk of developing the disorder.
“This study highlights the need for a greater understanding of the biological sex mechanisms that contribute to Alzheimer's disease progression so we can develop more effective therapeutic interventions,” said Kevin Hascup, PhD, principal investigator of the study.
Targeting Senescent Cells Early
The two drug combinations, Dasatinib and Quercetin (D+Q) and a compound called Fisetin, were administered monthly. Researchers measured various health indicators, including blood sugar levels, energy use, memory, and biomarkers of Alzheimer’s.
Both treatments target senescent cells. As people age, cells in their bodies can become "senescent," which means they stop performing normal functions and start releasing harmful substances, damaging neighboring healthy cells. These senescent cells can build up in the brain and body, contributing to aging and diseases like Alzheimer's.
In the study — whose lead author is Yimin Fang, PhD — female mouse models with the D+Q treatment showed fewer signs of senescence and less amyloid-beta, a protein that forms plaques in the brains of people with Alzheimer's disease. This led to improved spatial memory, which means they performed better in tasks that required remembering locations, such as remembering the route home from the grocery store.
The treatments did not have the same positive effects in male mice. In fact, some markers of senescence and inflammation actually increased with the D+Q treatment in male mice.
Fisetin did not have a significant impact on most measures in female mice. However, it did help to reduce some markers of inflammation in the blood. In male mice, Fisetin had minimal effects and did not significantly improve their condition.
Other studies surrounding clearing senescent cells have been conducted during later disease stages, but the Hascup lab explored whether removing these senescent cells during early development of Alzheimer’s could improve memory and other metabolic functions that worsen disease progression.
Advancing personalized research and treatment
Historically, research when exploring new treatments has been limited to only male models, but the Hascup lab has been exploring different reactions to treatment from both males and females. Considering around two-thirds of diagnosed Alzheimer’s patients are women, the lab is exploring discrepancies between the sexes and how personalized treatments could provide better results.
This research builds off of previous studies surrounding senolytic treatment and exploring differing effects depending on sex. However, results were flipped. In that study, male mouse models showed favorable responses to Fisetin while female mouse models showed no difference, and actually showed detrimental effects to D+Q.
An accelerated pathological disease progression in female mice may account for a more pronounced response to D+Q treatment, underscoring the necessity for personalized approaches in developing Alzheimer's disease therapies that consider both sex and the stage of disease progression. The different findings seen in female Alzheimer’s mice and their healthy siblings suggests that if a certain level of senescent cells is not present, the D+Q treatment may actually cause harm rather than aid.
Further studies are needed to understand why these differences occur and how tailored treatments for both men and women could lead to better, more personalized therapies for people with Alzheimer's disease in the future.
This work was supported by the National Institutes of Health, the Dale and Deborah Smith Center for Alzheimer’s Research and Treatment, and the Kenneth Stark Endowment.
