Researchers have discovered that glucose metabolism in the brain is disrupted in aging brains and neurodegenerative conditions like Alzheimer’s and Parkinson’s. They identified an enzyme, indoleamine-2,3-dioxygenase 1 (IDO1), that regulates these changes and found that blocking this enzyme could preserve memory and cognition in the early stages of Alzheimer’s disease. Through experiments on mice models, they found that an immunotherapy cancer drug can block this pathway and restore function in affected areas of the brain, particularly the hippocampus. The findings were published in Science and suggest that IDO1 inhibitors currently in development for cancer treatment could be repurposed for treating neurodegenerative diseases.
The team of researchers from Stanford University, Kyoto University, Princeton University, Salk Institute, and Penn State studied the effect of an enzyme present in astrocytes on neuron signaling in the hippocampus. Neurons in the brain rely on lactate fuel, whose production is regulated by the molecule kynurenine. The conversion of amino acid tryptophan to kynurenine, facilitated by IDO1, plays a role in brain aging and neurodegenerative diseases. The team discovered that increases in IDO1 activity in astrocytes near amyloid beta and tau proteins in Alzheimer’s patients led to a drop in glucose metabolism. By using a cancer drug to block IDO1 activity in mouse models of Alzheimer’s, they successfully improved memory in these mice, indicating the potential for this drug to be effective in treating early-stage Alzheimer’s disease.
Experiments on human brain tissues, including those from Alzheimer’s patients, showed an increase in KYN but not TRP in patients who had worse dementia symptoms. This indicates a potential link between disrupted glucose metabolism and dementia severity in Alzheimer’s disease. Furthermore, human induced pluripotent stem cell-derived astrocytes from late-onset Alzheimer’s patients exhibited normalized glucose metabolism after IDO1 inhibition with the cancer drug. The team hopes to further investigate this mechanism in astrocytes from different patient groups in the future. David Merrill, a geriatric psychiatrist, expressed excitement over the potential for metabolic interventions, such as metformin, ketogenic diets, or GLP-1 agonists, in treating neurodegenerative conditions like Alzheimer’s and Parkinson’s.
The researchers initially focused on the immune mechanisms involved in brain injury before delving into the inflammatory pathway associated with prostaglandin E2 and kynurenine metabolism regulated by IDO1. They discovered that IDO1 activity was localized in astrocytes but not neurons in mice models, particularly in the presence of amyloid beta and tau proteins. By blocking IDO1 activity using the cancer drug PF068, they observed an increase in glycolysis and mitochondrial respiration in astrocytes, leading to improved memory in mouse models of Alzheimer’s disease. Subsequent analysis of hippocampal tissues revealed that KYN increase associated with amyloid beta accumulation was blocked by the drug, further confirming the role of IDO1 inhibition in preserving memory function in Alzheimer’s.
The team’s findings suggest that disruption of the metabolic pathway involving IDO1 and kynurenine may contribute to the glucose metabolism changes observed in Alzheimer’s disease. By targeting this pathway with IDO1 inhibitors, researchers hope to accelerate the development of treatments for neurodegenerative diseases like Alzheimer’s and Parkinson’s in their early stages. Further studies on patient-derived astrocytes from different age groups and neurological conditions are planned to validate these findings. The potential for metabolic interventions in neurodegenerative diseases, based on the regulation of glucose metabolism, is an exciting area of active clinical research that could revolutionize the treatment of these conditions in the future.
