A class of drugs intended to fight cancer could be used to treat neurodegenerative diseases such as Alzheimer’s, as a study has found they could restore brain function and memory.
A type of drug originally developed to treat cancer could be a promising new therapeutic option for neurodegenerative diseases such as Alzheimer’s, according to a study by researchers at Penn State, Stanford University and an international team of collaborators.
Researchers found that by blocking a specific enzyme called indoleamine-2,3-dioxygenase 1 (IDO1), they could restore memory and brain function in models that mimic Alzheimer’s disease. The findings have been published in the journal Science and suggest that IDO1 inhibitors, currently in development to treat various types of cancer, including melanoma, leukemia and breast cancer, could be repurposed to treat early stages of neurodegenerative diseases, which would represent a significant advance in the treatment of these chronic pathologies that lack preventive therapies.
“We are showing that IDO1 inhibitors, which are already in the pipeline for cancer treatments, have great potential to target and treat Alzheimer’s,” said Melanie McReynolds, the Dorothy Foehr Huck and J. Lloyd Huck Professor of Biochemistry and Molecular Biology at Penn State and co-author of the paper.
“In the broader context of aging, neurological decline is one of the biggest factors impeding healthy aging. Understanding and treating metabolic decline in neurological disorders will benefit not only those who are diagnosed, but also our families, society and the economy at large.”
Protecting the brain from aging and neurodegeneration
Alzheimer’s disease is the most common form of dementia, a term that encompasses all neurodegenerative disorders associated with aging, McReynolds said. “Inhibiting this enzyme, particularly with compounds that have already been investigated in human clinical trials for cancer, could be a major step toward finding ways to protect our brains from damage caused by aging and neurodegeneration,” said Katrin Andreasson, professor of neurology and neurological sciences at Stanford University School of Medicine and senior author of the study.
Alzheimer’s affects the areas of the brain responsible for thinking, memory and language, resulting from the progressive and irreversible loss of synapses and neural circuits. As the disease progresses, symptoms can worsen from mild memory loss to the inability to communicate and respond to the environment. Alzheimer’s treatment focuses on managing symptoms and slowing progression by targeting the buildup of amyloid and tau plaques in the brain, but there are no approved treatments to combat the onset of the disease, according to McReynolds.
“We are showing that by focusing on brain metabolism we can not only slow down, but reverse the progression of Alzheimer’s disease”
“Scientists have focused on the long-term effects of what we identified as a problem in the way the brain fuels itself,” said Praveena Prasad, a doctoral student at Penn State and co-author of the study. “Currently available therapies try to remove peptides that are likely the result of a larger problem that we can address before these peptides begin to form plaques. We are showing that by targeting brain metabolism we can not only slow, but reverse the progression of this disease.”
Using preclinical models—in vitro cell models with amyloid and tau proteins, in vivo mouse models, and in vitro human cells from Alzheimer’s patients—the researchers showed that stopping the action of IDO1 helps restore healthy glucose metabolism in astrocytes, the star-shaped cells in the brain that provide metabolic support to neurons.
IDO1 is an enzyme that breaks down tryptophan, a molecule that can cause drowsiness, into a compound called kynurenine. The production of kynurenine in the body is the first part of a chain of reactions known as the kynurenine pathway (KP), which plays a crucial role in providing cellular energy to the brain. The researchers found that when IDO1 generated too much kynurenine, it reduced glucose metabolism in astrocytes, which was necessary to fuel neurons. By suppressing IDO1, metabolic support for neurons was increased and their ability to function was restored.
The study was conducted in several models of Alzheimer’s disease, specifically amyloid or tau accumulation, and the researchers found that the protective effects of blocking IDO1 extended to these two different pathologies. Their findings suggest that IDO1 might also be relevant in diseases with other types of pathologies, such as Parkinson’s disease-associated dementia, as well as in the broad spectrum of progressive neurodegenerative disorders known as tauopathies, explained Paras Minhas, a current resident at Memorial Sloan Kettering Cancer Center and the senior author of the study.
“The brain relies heavily on glucose to carry out many processes, so losing the ability to effectively use glucose for metabolism and energy production can trigger metabolic decline and, in particular, cognitive impairment,” Minhas said. “Through this collaboration, we were able to accurately visualize how brain metabolism is affected by neurodegeneration.”
