A type of drug developed to treat cancer shows promise as a new treatment for neurodegenerative diseases such as Parkinson’s, according to a study by researchers at Penn State, Stanford University and an international team of collaborators.Alzheimer.
New Hope for Alzheimer’s
Researchers found that by blocking a specific enzyme called indolamine-2,3-dioxygenase 1, or IDO1 for short, they could rescue memory and brain function in models that mimic Alzheimer’s disease.
The results, published in the journal Science suggest that IDO1 inhibitors currently in development as treatments for many types of cancer, including melanoma, leukemia and breast cancer, could be repurposed to treat the early stages of neurodegenerative diseases, a first for chronic conditions for which there are no preventative treatments.
“We are demonstrating that IDO1 inhibitors, which are already in the pipeline for cancer drugs, have great potential to target and treat Alzheimer’s disease,” said Melanie McReynolds, the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State and a co-author of the study.
“In the broader context of aging, neurological decline is a major cofactor in the failure to age more healthily. The benefits of understanding and treating metabolic decline in neurological disorders will impact not only those diagnosed, but our families, our society, our entire economy.”
Alzheimer’s disease is the most common type of dementia, an umbrella term for all age-related neurodegenerative disorders, McReynolds explained. As of 2023, as many as 6.7 million Americans were living with Alzheimer’s disease, according to the Centers for Disease Control and Prevention, and its prevalence is expected to triple by 2060.
“Inhibiting this enzyme, particularly with compounds that have previously been studied in human clinical trials for cancer, could be a major step forward in finding ways to protect our brains from the damage caused by aging and neurodegeneration,” said Katrin Andreasson, MD, PhD, the Edward F. and Irene Pimley Professor of Neurology and Neurological Sciences at Stanford University School of Medicine and lead author of the study.
Alzheimer’s disease affects the parts of the brain that control thinking, memory, and language, due to the progressive and irreversible loss of synapses and neural circuits.
As the disease progresses, symptoms can range from mild memory loss to the loss of the ability to communicate and respond to the environment. Current treatments for the disease focus 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, McReynolds said.
“The scientists targeted the downstream effects of what we identify as a problem with the way the brain fuels itself,” said Praveena Prasad, a doctoral student at Penn State and co-author of the study.
“Currently available therapies are working to remove peptides that are likely the result of a larger problem that we can target before those peptides can start to form plaques. We’re showing that by targeting the brain’s metabolism, we can not only slow but reverse the progression of this disease.”
Using preclinical models (in vitro cellular models with amyloid and tau proteins, in vivo mouse models, and in vitro human cells from Alzheimer’s patients), the researchers demonstrated that disrupting IDO1 helps restore healthy glucose metabolism in astrocytes, the star-shaped brain cells that provide metabolic support to neurons.
IDO1 is an enzyme that breaks down tryptophan, the same molecule in turkey that can put you to sleep, into a compound called kynurenine. The body’s production of kynurenine is the first part of a chain reaction known as the kynurenine pathway, or KP, which plays a critical role in how the body provides cellular energy to the brain.
The researchers found that when IDO1 generated too much kynurenine, it reduced glucose metabolism in astrocytes, which are needed to fuel neurons. With IDO1 suppressed, metabolic support for neurons increased and their ability to function was restored.
The researchers conducted the study on several models of Alzheimer’s disease, specifically the accumulation of amyloid or tau, and found that the protective effects of IDO1 blockade are common to these two different pathologies.
Their findings suggest that IDO1 may also be relevant in diseases with other types of pathology, such as Parkinson’s disease and dementia, as well as in the broad spectrum of progressive neurodegenerative disorders known as tauopathies, said Paras Minhas, a current resident at Memorial Sloan Kettering Cancer Center who earned a combined medical degree and doctorate in neuroscience from Stanford School of Medicine and is the paper’s first author.
“The brain is very dependent on glucose to fuel many processes, so losing the ability to effectively use glucose for metabolism and energy production can trigger metabolic decline and, in particular, cognitive decline,” Minhas said. “Through this collaboration, we were able to precisely visualize how brain metabolism is affected by neurodegeneration.”
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