Researchers at Weill Cornell Medicine have uncovered a new clue in understanding how dementia develops—and their discovery could point to an entirely new way to treat it.
The study, published in Nature Metabolism, reveals that damaging molecules called free radicals, long linked to aging and brain disease, are produced not inside neurons as once thought but inside neighboring astrocytes, a type of brain cell that supports neurons.
By pinpointing the exact source of these molecules, scientists say it may now be possible to block their harmful effects without disrupting the brain’s normal functions.
“We can now target specific mechanisms and go after the exact sites that are relevant for disease,” said Dr. Anna Orr, co-leader of the research and the Nan and Stephen Swid Associate Professor of Frontotemporal Dementia Research at Weill Cornell.
Free radicals, also known as reactive oxygen species (ROS), are unstable molecules that are byproducts of the body’s energy production process.
Inside cells, this process takes place in tiny structures called mitochondria—often referred to as the cell’s powerhouses.
While low levels of ROS help cells function properly, excess amounts can damage DNA, proteins, and other vital molecules, leading to inflammation and cell death.
For years, scientists have suspected that mitochondrial ROS contribute to neurodegenerative diseases such as Alzheimer’s and frontotemporal dementia.
Many studies have tested antioxidants to neutralize ROS, but the results have been disappointing.
“Most antioxidants failed in clinical trials because they can’t stop ROS at the source,” explained Dr. Adam Orr, an assistant professor of neuroscience and co-leader of the study. “They also tend to disrupt normal cell metabolism.”
To overcome this limitation, Dr. Orr developed a new drug-screening system to find molecules that could block ROS production at specific mitochondrial sites—without affecting other healthy functions.
His team identified a class of compounds called S3QELs (“sequels”), which can precisely suppress ROS from a part of the mitochondria known as Complex III.
When the researchers tested these compounds in cell cultures, they made a surprising discovery: the damaging ROS weren’t coming from neurons at all, but from astrocytes.
These non-neuronal cells, which normally support and protect neurons, began producing large amounts of ROS when exposed to inflammatory signals or dementia-related proteins like amyloid-beta. When the researchers added S3QELs, ROS levels dropped, inflammation was reduced, and neurons were protected.
Further tests in a mouse model of frontotemporal dementia confirmed these findings. Treatment with S3QELs reduced astrocyte activation, lowered inflammatory gene activity, and even decreased abnormal tau protein changes that are characteristic of dementia.
Remarkably, the therapy worked even when given later in the disease process, improving survival in mice without apparent side effects.
“The precision of these mechanisms had not been previously appreciated,” said Dr. Anna Orr. “It suggests that specific triggers in brain cells can produce ROS from specific mitochondrial sites to affect particular targets.”
The team is now working with medicinal chemist Dr. Subhash Sinha to refine these compounds into potential drugs. They also plan to study how genetic risk factors for dementia might alter ROS production in the brain.
“This study has changed how we think about free radicals,” said Dr. Adam Orr. “By understanding where they come from and how they act, we can finally begin to design treatments that stop brain inflammation and neurodegeneration at their root cause.”
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