A Fisetin Variant, CMS121, Slows Disease Progress in an Alzheimer's Mouse Model
The research materials here are of interest because fisetin has been shown to be a senolytic compound in mice, capable of selectively destroying harmful senescent cells. Other senolytics have reversed the progression of Alzheimer's disease pathology in mouse models of the condition. Destroying senescent cells in the brain reduces inflammatory signaling, and chronic inflammation is a significant mechanism in neurodegenerative conditions such as Alzheimer's disease. Whether this compound works well as a senolytic in humans has yet to be established - a clinical trial is underway, so hopefully we'll find out in the next year or two.
The researchers here are not interested in cellular senescence at all, however, and instead base their work on the effects of fisetin and fisetin-like molecules on lipid metabolism in the brain. Back in 2014, they showed that fisetin slowed the onset of Alzheimer's like symptoms in mice. The present work is much the same, except with an improved version of fisetin called CMS121. This all raises the question of whether their approach is working for the reasons that they think it is working.
Over the last few decades, researchers have studied how a chemical called fisetin, found in fruits and vegetables, can improve memory and even prevent Alzheimer's-like disease in mice. More recently, the team synthesized different variants of fisetin and found that one, called CMS121, was especially effective at improving the animals' memory, and slowing the degeneration of brain cells.
In the new study, researchers tested the effect of CMS121 on mice that develop the equivalent of Alzheimer's disease. The team gave a subset of the mice daily doses of CMS121 beginning at 9 months old - the equivalent of middle age in people, and after the mice have already begun to show learning and memory problems. The timing of the lab's treatment is akin to how a patient who visits the doctor for cognitive problems might be treated, the researchers say. After three months on CMS121, at 12 months old, the mice were given a battery of memory and behavior tests. In both types of tests, mice with Alzheimer's-like disease that had received the drug performed equally well as healthy control animals, while untreated mice with the disease performed more poorly.
To better understand the impact of CMS121, the team compared the levels of different molecules within the brains of the three groups of mice. They discovered that when it came to levels of lipids - fatty molecules that play key roles in cells throughout the body - mice with the disease had several differences compared to both healthy mice and those treated with CMS121. In particular, the researchers pinpointed differences in something known as lipid peroxidation - the degradation of lipids that produces free radical molecules that can go on to cause cell damage. Mice with Alzheimer's-like disease had higher levels of lipid peroxidation than either healthy mice or those treated with CMS121.