Boosting brain metabolism restores memory in mice with Alzheimer’s disease : Shots

The brain requires far more energy to function properly than any other organ in the body, and both aging and Alzheimer’s disease appear to sap the brain’s power.

But an experimental anti-cancer drug appears to revitalize the brains of mice with a form of Alzheimer’s disease, even restoring their learning and memory.

The findings, published in Science, suggest that drugs that boost the brain’s metabolism may eventually be able to reverse some of the symptoms of Alzheimer’s disease.

The findings also suggest a treatment that is different from any currently on the market. Drugs currently used to treat Alzheimer’s, such as lecanemab and donanemab, target the sticky amyloid plaques that build up in patients’ brains. These drugs can remove plaques and slow the progression of the disease, but they cannot improve memory or thinking skills.

Shannon McCauley, an associate professor at the University of Kentucky who was not involved in the study, said the results should help “change the way we think about targeting this disease.”

Surprises and discoveries

The new research was sparked by a lab experiment that didn’t go as planned.

The Stanford team was studying an enzyme called IDO1, which plays a key role in maintaining normal cellular metabolism, and they suspected that in Alzheimer’s disease, its dysfunction limits the brain’s ability to turn nutrients into energy.

So the team used genetics to completely remove the enzyme from mice with a form of Alzheimer’s disease, suggesting that without IDO1, brain metabolism slows down.

“We expected everything to get much, much worse,” says Dr. Katrin Andreasson, a professor of neurology and neuroscience at Stanford University, “but it was the exact opposite.”

Without this enzyme, the mice’s brains actually became better at turning glucose into energy, and they did not experience the memory loss that typically accompanies Alzheimer’s disease.

“This was a very significant rescue operation, so we went back and re-planned and tried to understand what was going on,” Andreasson said.

Eventually, the team found an explanation.

Removing the enzyme changed the behavior of cells called astrocytes.

Normally, astrocytes help supply energy to neurons, the cells that enable learning and memory, but when Alzheimer’s toxic plaques and neurofibrillary tangles start to appear in the brain, levels of IDO1 increase and astrocytes stop doing this.

“They’re in a sort of sleep state,” Andreasson says, “and we have to wake them up to help their neurons.”

That’s exactly what happened when scientists used genetics to remove IDO1.

Their hypothesis was that high levels of IDO1 limit the ability of astrocytes to produce lactate, a chemical that helps brain cells, including neurons, convert food into energy.

To test this hypothesis, a team led by Dr Paras Minhas conducted a series of experiments, one of which involved placing a mouse in the centre of a shiny white disk under a bright light.

“You really want to get out of there,” Andreasson says, “but you have to follow the visual cues and remember where the escape route is.”

With just a few days of training, healthy mice learned to read those cues and were able to escape almost instantly.

“But in the Alzheimer’s mice, the time it took to find the escape route really increased dramatically,” Andreasson says.

That changed when the team treated the mice with an experimental cancer drug that could block the enzyme in a way that is almost identical to genetic engineering.

The treated mice learned to escape bright light as quickly as healthy animals, and observations of their brains showed that astrocytes were awakening and helping neurons generate the energy needed for memory and thought.

In the hippocampus, a brain region crucial for memory and navigation, trials showed that the drug restored normal glucose metabolism, even though Alzheimer’s plaques and neurofibrillary tangles were still present.

The team also tested human astrocytes and neurons taken from Alzheimer’s patients, and again, the drug restored normal function.

Beyond plaque and gingival tangles

This experiment adds to the evidence that Alzheimer’s disease involves many contributing factors beyond the appearance of plaques and neurofibrillary tangles.

“These metabolic changes occur in our brains, but they are reversible,” MacAulay says.

Neurons have long been the focus of Alzheimer’s disease research, but new findings suggest that other types of cells in the brain may also play important roles in the disease.

The brain is like a beehive, with neurons as the queen bees, says MacAuley, but as Alzheimer’s changes the brain, worker bees like astrocytes are called upon to do more.

“Worker bees are incredibly overtaxed with all the work that’s being asked of them,” MacAulay said, “and then the whole system just doesn’t work.”

Metabolic therapies that restore astrocytes and other helper cells in the brain could one day boost the effectiveness of existing Alzheimer’s drugs that clear amyloid plaques, McCauley says.

And metabolic approaches could improve memory and thinking, something amyloid drugs cannot do.

“Maybe this will make the astrocytes and neurons work a little better, and the body function a little better,” MacAulay says.

But first, she says, the promising results need to be replicated in humans.