Scientists at Weill Cornell Medicine have discovered that harmful molecules known as free radicals—produced inside specific brain cells called astrocytes—could play a major role in the development of dementia.
The study, published in *Nature Metabolism*, revealed that when researchers blocked free radical production in these cells, they were able to reduce inflammation and protect neurons from damage.
The findings suggest a promising new way to treat neurodegenerative diseases such as frontotemporal dem.
Astrocytes are support cells that play a crucial role in maintaining healthy brain function. They supply energy to neurons, help regulate blood flow, and remove waste. But under stress, astrocytes can become overactive and start releasing harmful substances that contribute to inflammation and neuronal injury.
The Weill Cornell team found that one of these harmful agents is a type of free radical generated by mitochondria—the tiny structures inside cells that produce energy.
Mitochondria are often described as the “powerhouses” of the cell. They convert nutrients into energy that powers all cellular processes. During this process, they naturally release small amounts of reactive oxygen species (ROS), commonly known as free radicals. In normal amounts, ROS are useful because they help regulate cellular activity.
But when mitochondria produce too many free radicals, they can damage proteins, DNA, and cell membranes. This oxidative stress has long been linked to aging and neurode.
Dr. Adam Orr, one of the study’s lead authors, explained that many previous attempts to treat brain diseases with antioxidants failed because they could not reach or precisely target the areas where free radicals are made. “Antioxidants can’t easily block ROS at their source without also interfering with how cells produce energy,” he said.
To solve this problem, his team developed a new drug discovery platform that could find compounds capable of blocking free radical production only at specific mitochondr…
The scientists focused on a particular energy-producing site in mitochondria called Complex III.
This site is known to be a major source of ROS that can leak into the rest of the cell and cause damage. Surprisingly, the researchers discovered that most of these harmful free radicals didn’t come from neurons—the cells responsible for thinking and memory—but from astrocytes, the brain’s support cells.
To test their theory, the team used molecules called S3QELs (pronounced “sequels”), which can block free radical production specifically at Complex III. When they treated brain cells with S3QELs, they found that neurons were protected from damage, but only when astrocytes were present.
This finding showed that free radicals from astrocytes were a key cause of neuronal injury. Further tests revealed that when astrocytes were exposed to inflammation or dementia-related proteins such as amyloid-beta.
Dr. Anna Orr, who co-led the study, described how the research changed their understanding of brain inflammation. “The precision of these mechanisms had not been previously appreciated,” she said. “Specific triggers appear to cause ROS production from specific mitochondrial sites, and these signals then affect certain proteins and genes involved in dementia.”
To confirm their findings, the researchers treated mice engineered to develop frontotemporal dementia with the S3QEL compound. The treated mice showed reduced inflammation, fewer signs of tau protein buildup (a hallmark of dementia), and improved overall brain health.
Remarkably, these benefits appeared even when the treatment started after symptoms had already developed. The therapy was well tolerated, showed no major side effects, and even extended the animals’ lifespan.
The team is now working to refine and test the S3QEL compounds in collaboration with medicinal chemist Dr. Subhash Sinha at Weill Cornell. They hope to understand whether genes associated with dementia alter how mitochondria produce free radicals, and if some people’s genetic makeup might make them more vulnerable to this process.
Dr. Adam Orr said the research could reshape how scientists view free radicals. “This work changes our thinking about oxidative stress in the brain,” he said. “It shows that not all free radicals are the same—and that by targeting the right ones, in the right place, we can protect brain cells without disrupting normal metabolism.”
This discovery could open a new frontier in dementia research. By pinpointing the exact cellular sources of damage, scientists may be able to design safer, more effective drugs that preserve brain function for longer.
While more studies are needed, the results represent a major step toward understanding—and potentially treating—the root causes of neurodegenerative diseases.
If you care about dementia, please read studies that eating apples and tea could keep dementia at bay, and Olive oil: a daily dose for better brain health.
For more health information, please see recent studies what you eat together may affect your dementia risk, and time-restricted eating: a simple way to fight aging and cancer.
The study is published in Nature Metabolism.
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