Could a cancer drug help treat early Alzheimer’s? Study offers clues

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Glucose metabolism is understood to be disrupted in aging brains, particularly in neurodegenerative conditions like Alzheimer’s and Parkinson’s.
Researchers have identified an enzyme that regulates glucose metabolism in the brain and discovered that a cancer drug may help treat early-stage Alzheimer’s.
Treatment with the cancer drug restored function in the hippocampus in an Alzheimer’s mouse model.
It has long been understood that glucose metabolism in the brain is disrupted by aging and neurodegenerative diseases.
Researchers have identified an enzyme that regulates glucose metabolism changes in the brain occurring in conditions like Alzheimer’s disease (AD) and Parkinson’s disease (PD).
Alzheimer’s disease (AD)
Parkinson’s disease (PD)
Using an Alzheimer’s mouse model, they found that blocking the enzyme, called indoleamine-2,3-dioxygenase 1, or IDO1, helped preserve memory and cognition in the early stages of the disease.
They discovered that an immunotherapy cancer drug could block this pathway, restoring function to affected areas of the brain. The findings were recently published in Science.
immunotherapy
Science
IDO1 inhibitors are currently in development for treating various types of cancer, such as melanoma, leukemia, and breast cancer. Researchers say their findings could help speed up these drugs to market and be repurposed to treat neurodegenerative diseases in their early stages.
melanoma
leukemia
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Targeting an enzyme to slow Alzheimer’s progression
For the study, researchers from Stanford University, Kyoto University, Princeton University, Salk Institute, and Penn State examined the effect of an enzyme present in the astrocytes on neuron signaling in the hippocampus, a part of the brain that’s responsible for memory and learning.
Neurons in the brain are fueled with lactate, the production of which is regulated by the molecule kynurenine.
IDO1 is an enzyme that plays a role in the conversion of the amino acid tryptophan (TRY) to kynurenine (KYN). KYN is known to play a role in brain aging and neurodegenerative disease.
This conversion produces downstream metabolites that play a role in immune regulation. This pathway was what the team had been previously investigating, but this time they looked at the enzyme IDO1.
The team had originally been investigating the immune mechanisms underpinning brain injury, when they decided to explore an inflammatory pathway associated with prostaglandin E2.
prostaglandin
While looking at the metabolism of TRY into KYN they found that the enzyme IDO1, which regulates this metabolic pathway, behaved differently than expected in a mouse model of Alzheimer’s, corresponding study author Katrin Andreasson, MD, professor of neurology and neurological sciences at Stanford University, told Medical News Today.
Katrin Andreasson, MD
“We tested what we thought would be the role of IDO1 in a model of amyloid accumulation in mice, and we found the complete opposite than we had expected. That naturally piqued our interest, so we drilled down and found that this path was very important in a very different cell type, which is the astrocyte. Not so much in the immune cells. That’s how we then zeroed in on astrocytes and their metabolic support of neurons.”
— Katrin Andreasson, MD, study co-author
Cancer drug regulates glucose metabolism in Alzheimer’s
Researchers identified IDO1 activity in astrocytes, but not neurons, taken from mice. This suggested that the pathway they were investigating only occurred in these cells.
They hypothesized that the enzyme IDO1 would be increased in astrocytes in the presence of amyloid beta and tau, two proteins that are present in people with Alzheimer’s disease.
They found that genes responsible for the expression of IDO1 increased significantly in mouse astrocytes exposed to amyloid beta and tau proteins. They also discovered that a subsequent increase in KYN led to a drop in glucose metabolism in astrocytes.
tau proteins
The findings confirmed the researchers’ hypothesis that disruption of the homeostasis of this pathway could play a role in the disruption of glucose metabolism seen in people with Alzheimer’s.
Further experiments in mice neurons in the lab showed use of a cancer immunotherapy drug that blocks IDO1 activity, PF068, resulted in an increase in glycolysis and mitochondrial respiration in astrocytes but not neurons, in a dose-dependent manner.
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Next, the researchers administered the cancer drug to mouse models of Alzheimer’s disease for a month and tested the memory of the mice using the maze test.
The results showed the drug could improve memory in mice. Further analysis of their hippocampal tissues showed that the KYN increase seen in mouse models of Alzheimer’s with accumulation of amyloid beta was blocked by PF068. This suggests that the rescuing of the memory of these mice when exposed to the drug was due to its disruption of this pathway.
Further experiments were done on human brain tissues, including from people with Alzheimer’s disease, which showed an increase of KYN, but not TRP in patients who had died with worse dementia symptoms.
Researchers also created human induced pluripotent stem cell (iPSC)–derived astrocytes from patients with late-onset Alzheimer’s, which showed that the deficit in glucose metabolism was normalized after IDO1 inhibition with PF068.
Andreasson said the team hoped to look at patient-derived astrocytes in younger and older patients, and those with different neurological conditions in the future, to investigate this mechanism in those groups.
Glucose metabolism: A therapeutic target for Alzheimer’s?
David Merrill, MD, PhD, a board-certified geriatric psychiatrist at Providence Saint John’s Health Center in Santa Monica, CA, and Singleton Endowed Chair in Integrative Brain Health told MNT he would be pleased to see clinical trials for metabolic interventions for Alzheimer’s.
David Merrill, MD, PhD
“Altered glucose metabolism is implicated in Parkinson’s, Huntington’s, and multiple sclerosis. We see that changes in glucose metabolism may contribute to the neurodegenerative changes seen in other neurological conditions,” Merrill said.
“We may see benefit from using metformin, ketogenic diets, or GLP-1 agonists. This is an exciting area of active clinical research.”
metformin