Scientists expose secret brain trigger behind dementia

Scientists have identified a new culprit in the development of dementia: free radicals from specific regions of star-shaped brain support cells called astrocytes.

Researchers at Weill Cornell Medicine in New York focused their research on mitochondria, tiny structures in astrocytes and other cells that take nutrients from food and convert them into chemical energy.

While mitochondria produce most of the energy the body needs to function, they also release reactive oxygen species (ROS), known as free radicals. At normal levels, ROS help regulate basic cell functions, but excessive or poorly timed production can damage cells.

In diseased astrocytes, external triggers such as inflammatory molecules or Alzheimer’s-linked amyloid-beta proteins caused a specific region in the mitochondria to overproduce ROS at the wrong time and place.

When the team administered a compound called S3QEL to mice modeling frontotemporal dementia, astrocytes became less active, inflammatory signals in the brain were reduced, and there was a reduction in tau proteins linked to dementia.

Remarkably, these effects occurred even when treatment began after dementia symptoms had begun.

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

The process is very targeted. It contains specific signals that activate free radicals in a specific location of the cell’s mitochondria and damage a selected set of proteins.

They gave the drug to mice by mixing it into their special food or injecting it. They then treated mice prone to dementia for several months. They looked for significant changes to see if the drug was working.

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

They also performed an experiment on extracted brain cells, including neurons, astrocytes and microglia, from mouse pups that had been genetically modified in the laboratory.

They bred mice with the genetic equipment to skip CIII. They then took culture samples of the astrocytes in their brains.

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

S3QEL compounds were specifically designed to target this pathway within mitochondria in hopes of reducing free radical production.

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

Graph shows survival advantage of sick treated mice [tauP301S (120) and tauP301S (240)] above mice receiving standard chow [tauP301S]. Survival also increased in healthy mice given the treatment [NTG (120) and NTG (240)] compared to those without it [NTG (0)]

But when they applied the experimental compound, this reaction diminished, similar to turning down the volume knob on a stereo.

The team then treated sick mice with S3QEL or a placebo and performed a series of tests assessing their movements, coordination, and overall activity levels over weeks to see whether the treatment improved their daily functions and symptoms.

Sick mice showed abnormal leg curling when held by the tail; this was a reflex indicating poor motor control, but the medication reduced it.

When mice were humanely euthanized, researchers found that the treated mice had lower markers of inflammation in their brains and less active microglia, the immune cells of the central nervous system.

They also had less toxic tau proteins, which are 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 separate and accumulate in toxic tangles inside neurons, eventually killing them.

In a separate group of mice that were not euthanized, treated mice lived 17 to 20 percent longer than mice that received a placebo.

Corresponding author Dr. Adam Orr said: ‘The study really changed the way we think about free radicals and opened up many new avenues of research.’

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

But recent findings from Weill Cornell have identified for the first time a new target: overactive astrocytes.

They suggest that effective treatment of neurodegenerative disease may involve not only clearing waste such as excess tau from neurons, but also calming the inflammation that allows damage to progress.

Although it will take years to develop and test a drug for human use, this study points to a future in which dementia can be managed with a targeted, well-tolerated drug that slows the devastating course of the disease.

Trial results were published in the journal Nature Metabolism.

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