Weill Cornell Medicine researchers report that free radicals generated at a specific mitochondrial site in astrocytes appear to promote neuroinflammation and neuronal injury in mouse models. Blocking those radicals with tailored compounds curbed inflammation and protected neurons. The findings, published Nov. 4, 2025, in Nature Metabolism, point to a targeted approach that could inform therapies for Alzheimer’s disease and frontotemporal dementia.
Scientists at Weill Cornell Medicine have identified a likely source of damaging brain inflammation in dementia: reactive oxygen species (ROS) produced at mitochondrial Complex III in astrocytes, the brain’s support cells. In cell and mouse experiments, inhibiting this ROS source reduced inflammatory signaling and preserved neurons, according to the study. (sciencedaily.com)
The team used small molecules called S3QELs (pronounced “sequels”) to selectively suppress Complex III–derived ROS without broadly disrupting mitochondrial function. In cultures, disease-linked triggers such as inflammatory factors and amyloid‑beta boosted astrocyte ROS, while S3QELs blunted the surge and limited downstream damage. “When we added S3QELs, we found significant neuronal protection but only in the presence of astrocytes,” said lead author Daniel Barnett. (news.weill.cornell.edu)
Why not simply give antioxidants? “Decades of research implicate mitochondrial ROS in neurodegenerative diseases,” said Dr. Adam Orr, who co-led the work, but many antioxidant trials have fallen short—likely because they don’t block ROS precisely at the source without altering normal metabolism, he noted. (sciencedaily.com)
In a mouse model of frontotemporal dementia, S3QEL treatment reduced astrocyte activation, dampened neuroinflammatory gene expression, and lowered a tau modification linked to disease—even when dosing began after symptoms emerged. Extended treatment improved survival, was well tolerated, and produced no obvious side effects. (news.weill.cornell.edu)
The paper, “Mitochondrial complex III–derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology,” was published in Nature Metabolism on Nov. 4, 2025 (DOI: 10.1038/s42255-025-01390-y). (lifescience.net)
“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 at Weill Cornell Medicine and a study co-leader. “We can now target specific mechanisms and go after the exact sites that are relevant for disease.” (sciencedaily.com)
According to Weill Cornell Medicine, the group plans to refine the S3QEL compounds with medicinal chemist Dr. Subhash Sinha and to probe how disease-associated genes shape mitochondrial ROS production and dementia risk. “The study has really changed our thinking about free radicals and opened up many new avenues of investigation,” Dr. Adam Orr said. (news.weill.cornell.edu)
