Published on: Nov 04, 2025
Researchers at Weill Cornell Medicine have uncovered a new link between free radicals produced in astrocytes—non-neuronal support cells in the brain—and the development of dementia. Their study, published on November 4 in Nature Metabolism, shows that blocking a specific site in these cells reduces brain inflammation and protects neurons, revealing a promising new therapeutic pathway for neurodegenerative diseases such as frontotemporal dementia and Alzheimer’s disease.
“I’m really excited about the translational potential of this work,” said Dr. Anna Orr, the Nan and Stephen Swid Associate Professor of Frontotemporal Dementia Research and co-lead author. “We can now target specific mechanisms and go after the exact sites that are relevant for disease.”
The team focused on mitochondria, the cell’s energy-producing structures that also emit reactive oxygen species (ROS)—molecules that are beneficial in small amounts but harmful when overproduced. While previous attempts to treat neurodegenerative diseases with antioxidants have largely failed, Dr. Adam Orr, co-lead author and assistant professor of research in neuroscience, believes that was because antioxidants couldn’t precisely block ROS at their source.
To address this, Dr. Orr developed a drug-discovery platform to identify molecules that selectively inhibit ROS generation from individual mitochondrial sites without disturbing overall metabolism. This led to the discovery of several small molecules known as S3QELs , which can specifically block ROS production at Complex III, a mitochondrial site known for releasing ROS into the rest of the cell.
Surprisingly, the researchers found that damaging ROS originated not from neurons but from astrocytes. When S3QELs were introduced, neurons showed significant protection—but only when astrocytes were present. Further experiments revealed that disease-related stimuli, including inflammatory molecules and amyloid-beta (a protein linked to Alzheimer’s), increased mitochondrial ROS production in astrocytes, which S3QELs successfully suppressed.
The team discovered that these ROS molecules oxidize key immune and metabolic proteins tied to neurological disorders and alter the activity of thousands of genes linked to brain inflammation and dementia.
The precision of these mechanisms had not been previously appreciated, especially not in brain cells, Dr. Anna Orr noted. It suggests a very refined process where specific triggers induce ROS from defined mitochondrial sites to impact precise cellular targets.
In a mouse model of frontotemporal dementia, treatment with S3QEL significantly reduced inflammation, decreased disease-related tau protein changes, and extended lifespan—even when administered after disease onset. The treatment was well-tolerated and showed no notable side effects, which the team attributes to its high specificity.
The researchers are now working with Dr. Subhash Sinha, a medicinal chemist at Weill Cornell, to further develop S3QELs as a potential new class of therapeutics. They also plan to investigate how genetic risk factors for neurodegenerative diseases influence ROS generation from specific mitochondrial sites.
This study has truly shifted our understanding of free radicals, said Dr. Adam Orr. It opens the door to new ways of studying—and potentially treating—neuroinflammation and neurodegeneration.
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