Researchers have discovered that glucose metabolism in the brain is disrupted in aging brains and neurodegenerative diseases like Alzheimer’s and Parkinson’s. They identified an enzyme called indoleamine-2,3-dioxygenase 1 (IDO1) that regulates these changes and found that blocking this enzyme helped preserve memory and cognition in an Alzheimer’s mouse model. By using an immunotherapy cancer drug to block this pathway, they were able to restore function in the hippocampus, an area responsible for memory and learning. The findings, published in Science, suggest that IDO1 inhibitors currently in development for cancer treatment could be repurposed to treat neurodegenerative diseases in their early stages.
In a study involving researchers from Stanford University, Kyoto University, Princeton University, Salk Institute, and Penn State, the team investigated the effect of the enzyme IDO1 in astrocytes on neuron signaling in the hippocampus. They found that IDO1 plays a role in the conversion of the amino acid tryptophan to kynurenine, which regulates the production of lactate that fuels neurons in the brain. Kynurenine has been linked to brain aging and neurodegenerative diseases, and the team discovered that inhibiting IDO1 in astrocytes could help normalize glucose metabolism disrupted in Alzheimer’s. Further experiments in mice showed that a cancer drug blocking IDO1 activity resulted in increased glycolysis and mitochondrial respiration in astrocytes, leading to improved memory in Alzheimer’s mouse models.
Investigating further, researchers found that IDO1 activity in astrocytes, not neurons, increased significantly in the presence of amyloid beta and tau proteins, both present in Alzheimer’s disease. This led to a decrease in glucose metabolism in astrocytes, confirming the disruption of this pathway in Alzheimer’s patients. Administering the cancer drug to mouse models of Alzheimer’s improved memory test results, and analysis of hippocampal tissues showed that the drug blocked the increase of kynurenine associated with amyloid beta accumulation. Experiments on human brain tissues, including those from Alzheimer’s patients, revealed an increase in kynurenine but not tryptophan in patients with worse dementia symptoms. Using human stem cell-derived astrocytes from Alzheimer’s patients also showed that IDO1 inhibition with the cancer drug normalized glucose metabolism deficits.
Dr. David Merrill, a geriatric psychiatrist at Providence Saint John’s Health Center, noted the potential for metabolic interventions in Alzheimer’s and other neurodegenerative conditions. He suggested that drugs like metformin, ketogenic diets, or GLP-1 agonists could be beneficial in targeting altered glucose metabolism in these diseases. Clinical trials for metabolic interventions in Alzheimer’s and other conditions could provide valuable insights into the role of glucose metabolism in neurodegeneration, offering new approaches to treatment. Understanding the mechanisms involved in the disruption of glucose metabolism in aging brains and neurodegenerative diseases could pave the way for novel therapeutic strategies to combat these conditions. By targeting enzymes like IDO1 and pathways that regulate glucose metabolism, researchers may be able to develop more effective treatments for Alzheimer’s, Parkinson’s, and other neurodegenerative diseases.
