Researchers have recently pinpointed a new factor contributing to dementia: free radicals originating from specific areas within astrocytes, which are star-shaped cells supporting brain function.

A team from Weill Cornell Medicine in New York has concentrated their efforts on mitochondria, the tiny powerhouses within astrocytes and other cells that transform nutrients into energy.

Although mitochondria supply the majority of the body’s energy, they also emit reactive oxygen species (ROS), commonly referred to as free radicals. Under normal circumstances, ROS aid in regulating vital cellular processes, but an overproduction can lead to cell damage.

In diseased astrocytes, external influences such as inflammatory molecules or amyloid-beta proteins associated with Alzheimer’s, prompted mitochondria to generate excessive ROS at inappropriate times and locations.

The researchers found that administering a compound named S3QEL to mice with a model of frontotemporal dementia reduced astrocyte activation, lowered inflammatory signals across the brain, and decreased tau proteins typically linked to dementia.

Notably, these beneficial effects were observed even when the treatment was initiated after the onset of dementia symptoms.

The team also reported that mice taking the experimental treatment in their food lived longer than the mice eating standard kibble without S3QEL.

The process is highly targeted. It involves specific signals that activate free radicals at a particular location in the cell’s mitochondria, causing harm to a select set of proteins. 

New research shifts the focus from clearing toxic proteins in neurons to calming overactive brain support cells as a promising new treatment strategy (stock)

They gave the drug to mice by either mixing it into their special food or injecting it. Then, they treated the dementia-prone mice for several months. To see if the drug was working, they looked for key changes.

They tested the mice’s behavior, such as their movement and coordination, to see if their symptoms improved. They also checked the mice’s brains under a microscope for signs of inflammation and damaging proteins after they died.

At the same time, they conducted an experiment in the lab on extracted brain cells, including neurons, astrocytes and microglia, taken from genetically-modified mouse pups. 

They bred mice to be genetically equipped to bypass CIII. Then, they took culture samples of astrocytes in their brains.

The team aimed to prove that their findings were specifically due to the Complex III (CIII) pathway in astrocytes, the specific process within the mitochondria where Complex III generates harmful free radicals that damage astrocytes in the brain and other cells throughout the body.

The S3QEL compounds were specifically designed to target this pathway within the mitochondria in the hopes of turning free radical production down.

Harmful free radicals emitted from astrocytes were found to activate genes known to drive brain inflammation. 

The graph shows the survival advantage that the sick treated mice [tauP301S (120) and tauP301S (240)] had over the mice that received standard chow [tauP301S]. Survival also improved in healthy mice given the treatment [NTG (120) and NTG (240)] compared to those without it [NTG (0)]

But when they administered the experimental compound, that reaction was reduced, similar to turning the volume knob down on a stereo.

The team then treated sick mice with S3QEL or a placebo and conducted a series of tests over weeks assessing their movement, coordination and overall activity levels to see if the treatment was improving their daily function and symptoms.

The sick mice had abnormal leg curling when held by the tail, a reflex indicating poor motor control, but the drug reduced this. 

When the mice were humanely euthanized, researchers found that treated mice has lower markers of inflammation in their brains and fewer activated microglia, the central nervous system’s immune cells.

They also had fewer toxic tau proteins, believed to play a primary role in the development of Alzheimer’s disease.

In healthy brain cells, tau helps stabilize internal structures. But in cases of dementia, they detach and clump into toxic tangles inside neurons, which eventually kills them.

In a separate cohort of mice that were not euthanized, the treated mice also lived 17 to 20 percent longer than their counterparts receiving the placebo.

Corresponding author Dr Adam Orr said: ‘The study has really changed our thinking about free radicals and opened up many new avenues of investigation.’

Currently, most Alzheimer’s treatments focus directly on the hallmark proteins, including tau and amyloid plaques in neurons.

But the latest findings out of Weill Cornell identified a new target, overactive astrocytes, for the first time.

They suggest that effective treatment for the neurodegenerative disease might not just be about clearing waste like excess tau from neurons, but about calming the inflammation that allows the damage to progress.

While it will take years to develop and test a drug for human use, this work points to a future where dementia could be managed by a targeted, well-tolerated medication that slows the disease’s devastating course.

Their trial results were published in the journal Nature Metabolism. 

An estimated seven million Americans are living with dementia. Around 6.7 million of those cases are Alzheimer’s dementia specifically.