Aging and Alzheimer’s disease starve the brain of energy. Now, scientists think they’ve found a way to boost brain metabolism — in mice.
PM Image/Getty Images
hide caption
convert caption
PM Image/Getty Images
The brain requires a lot of energy — more than any other organ in the body — to function properly. And aging and Alzheimer’s disease both seem to weaken the brain.
But an experimental cancer drug appears to be able to restore energy to the brains of mice with a form of Alzheimer’s disease—and even restore their ability to learn and remember.
Detect, published in magazine Sciencesuggests that it may eventually be possible to reverse some symptoms of Alzheimer’s disease in humans using drugs that boost brain metabolism.
The results also suggest a treatment approach unlike anything on the market today. Current drugs to treat Alzheimer’s, such as lecanemab and donanemab, target the sticky amyloid plaques that build up in patients’ brains. These drugs can clear the plaques and slow the progression of the disease, but do not improve memory or thinking.
The results will help “change the way we think about targeting this disease,” he said. Shannon Macaoleyan associate professor at the University of Kentucky who was not involved in the study.
A surprise, then a discovery
This new research comes after a lab experiment didn’t go as planned.
A team at Stanford studied an enzyme called IDO1 that plays a key role in maintaining normal cell metabolism. They suspect that in Alzheimer’s disease, IDO1 malfunctions in a way that limits the brain’s ability to convert nutrients into energy.
So the team used genetics to completely remove the enzyme from mice with a form of Alzheimer’s disease. They found that without any IDO1, brain metabolism would decline.
“We look forward to seeing everything [get] “Much, much, much worse,” he said. Dr. Katrin Andreassona professor of neurology and neuroscience at Stanford. “But no, quite the opposite.”
Without this enzyme, mouse brains actually metabolized glucose into energy better and did not exhibit the memory loss commonly seen in Alzheimer’s disease.
“It was such a profound rescue that we had to go back to the drawing board and try to figure out what was going on,” said Andreasson.
Finally, the team found an explanation.
Removing the enzyme changed the behavior of cells called astrocytes.
Normally, astrocytes help power neurons, the cells that enable learning and memory. But when the toxic plaques and tangles of Alzheimer’s begin to appear in the brain, IDO1 levels increase and astrocytes stop doing this job.
“They’re like sleeping,” says Andreasson. So “you have to wake them up to help the neurons.”
And that’s exactly what happened when scientists used genetics to knock out IDO1.
Their hypothesis is that high levels of IDO1 limit astrocytes’ ability to produce lactate, a chemical that helps brain cells, including neurons, convert food into energy.
To confirm the hypothesis, the research team led by Dr. Paras Minhasconducted a series of experiments. One experiment involved placing a mouse in the middle of a bright white plate under bright light.
“It really wants to get out of there,” Andreasson said. “But it has to learn where the escape route is” by following visual cues.
Healthy rats learned to read those signals after a few days of training and were able to escape almost immediately.
“But in mice with Alzheimer’s, escape route time actually skyrocketed,” says Andreasson.
That changed when the team gave the mice an experimental cancer drug that blocks the enzyme in a similar way to genetic engineering.
The treated mice learned to escape the bright light as quickly as healthy animals. And when they looked at their brains, they found that their astrocytes had woken up and were helping neurons produce the energy needed for memory and thinking.
In the hippocampus, a brain region important for memory and navigation, tests showed the drug restored normal glucose metabolism although Alzheimer’s plaques and tangles remained.
The team also tested human astrocytes and neurons derived from Alzheimer’s patients. And again, the drug restored normal function.
Beyond the plaque and tangles
Experiments add to growing evidence that Alzheimer’s disease involves more than just the appearance of plaques and tangles.
“We can have these metabolic changes in the brain, but they are reversible,” says Macaulay.
Neurons have long been the focus of Alzheimer’s research. But new findings also suggest that other types of cells in the brain may play an important role in the disease.
The brain is like a beehive, where one neuron is the queen, Macaulay says. But it is kept alive by worker bees, like astrocytes, that are called upon to do more as Alzheimer’s changes the brain.
“Those worker bees are under an unbelievable burden from all the things they’re being asked to do,” Macaulay said. “When that happens, the whole system doesn’t work well.”
Macauley said metabolic treatments that restore astrocytes and other support cells in the brain could one day enhance the effectiveness of existing Alzheimer’s drugs that clear amyloid plaques.
And the metabolic approach can improve memory and thinking — something amyloid drugs can’t do.
“Maybe this can help your astrocytes and neurons function a little better, so you can function a little better,” says Macaulay.
But first, she said, these promising results will have to be tested in humans.
