Scientists analyze major brain trigger behind dementia diagnosis
In this DML Report…
Researchers at Weill Cornell Medicine have identified excessive free radicals, specifically reactive oxygen species (ROS), produced at a precise site in the mitochondria of astrocytes—star-shaped brain support cells—as a key driver of dementia pathology. These ROS, generated through the Complex III (CIII) pathway, overactivate when triggered by inflammatory signals or amyloid-beta proteins, oxidizing immune and metabolic proteins, activating thousands of inflammation-related genes, and promoting overactive astrocytes that release inflammatory signals. This process leads to toxic modifications of tau proteins, causing them to detach from cellular structures, form tangles inside neurons, and ultimately kill brain cells, contributing to frontotemporal dementia and Alzheimer's disease.
In experiments, the team used compounds called S3QELs to selectively suppress ROS production at the CIII site without broadly disrupting mitochondrial function or antioxidant systems. In cell cultures from genetically modified mice, bypassing CIII confirmed astrocytes as the source of harmful ROS damaging themselves and nearby cells. In mice modeling frontotemporal dementia (tauP301S strain), administering S3QEL via food or injection for months reduced astrocyte activation, lowered brain-wide inflammatory markers and tau proteins, decreased activated microglia, and improved behavioral outcomes such as reduced abnormal leg curling, better movement, coordination, and activity levels.
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The treatment extended lifespan by 17-20% compared to placebo, even when started after symptoms appeared, and was well-tolerated with no notable side effects. Published November 4 in Nature Metabolism, the findings shift focus from clearing tau or amyloid in neurons to targeting astrocyte inflammation upstream. Lead researcher Dr. Adam Orr stated the study changes thinking on free radicals and opens new investigation avenues; co-lead Dr. Anna Orr highlighted translational potential for well-tolerated drugs slowing progression in Alzheimer's (affecting 6.7 million Americans) and related dementias.