The researchers found that by blocking a specific enzyme called indoleamine-2,3-dioxygenase 1, or IDO1 for short, they could rescue memory and brain function in models that mimic Alzheimer’s disease. The findings, published today (August 22) in the journal Science, suggest that IDO1 inhibitors currently in development as treatments for many cancers, including melanoma, leukemia and breast cancer, could be repurposed to treat the early stages of neurodegenerative diseases — a first for the chronic conditions for which no preventive treatments exist.

“We show that there is great potential for IDO1 inhibitors, which are already part of the repertoire of drugs being developed for cancer treatments, to target and treat Alzheimer’s,” 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 paper. “In the broader context of aging, neurological decline is one of the largest cofactors in failing to age more healthily. The benefits of understanding and treating metabolic decline in neurological diseases will impact not only those who are diagnosed, but also our families, our society and our entire economy.”

Alzheimer’s disease is the most common form of dementia, an umbrella term for all age-related neurodegenerative disorders, McReynolds explained. As many as 6.7 million Americans were living with Alzheimer’s in 2023, according to the Centers for Disease Control and Prevention, and its prevalence is expected to triple by 2060.

“Inhibiting this enzyme, particularly with compounds previously studied in human cancer clinical trials, could be a major step forward in finding ways to protect our brains from the damage caused by aging and neurodegeneration,” said Katrin Andreasson, 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 attacks the parts of the brain that control thought, memory and language, the result of a progressive and irreversible loss of synapses and neural circuits. As the disease progresses, symptoms can progress 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.

“Scientists are focusing on the downstream effects of what we identify as a problem with the way the brain controls itself,” said Praveena Prasad, a doctoral student at Penn State and co-author of the paper. “Therapies that are currently available work to remove peptides that are likely the result of a larger problem that we can address before those peptides have a chance to form plaques. We’re showing that by targeting the brain’s metabolism, we can not only slow the progression of this disease, but we can reverse it.”

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 showed that stopping IDO1 helps restore healthy glucose metabolism in astrocytes, the star-shaped brain cells that support neurons’ metabolism.

IDO1 is an enzyme that breaks down tryptophan, the same molecule in turkey that can make you sleepy, 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 crucial role in how the body delivers cellular energy to the brain. The researchers found that when IDO1 produced too much kynurenine, it reduced the glucose metabolism in astrocytes that was needed to power neurons. With IDO1 suppressed, metabolic support for neurons increased and their ability to function was restored.

The researchers conducted the study in different models of Alzheimer’s pathology, namely amyloid or tau accumulation, and found that the protective effects of blocking IDO1 cut across these two different pathologies. Their findings suggest that IDO1 may also be relevant in diseases with other types of pathology, such as Parkinson’s dementia and the broad spectrum of progressive neurodegenerative disorders known as tauopathies, explained Paras Minhas, a current resident at Memorial Sloan Kettering Cancer Center who earned a combined medical and doctoral degree 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 use glucose effectively for metabolism and energy production can cause metabolic decline and particularly cognitive decline,” Minhas said. “This collaboration allowed us to visualize exactly how brain metabolism is affected by neurodegeneration.”

The other Penn State author is lab manager Brenita Jenkins. Other co-authors are Amira Latif-Hernandez, Aarooran S. Durairaj, Qian Wang, Siddhita D. Mhatre, Travis Conley, Hannah Ennerfelt, Yoo Jin Jung, Edward N. Wilson, Frank M. Longo, Takeshi Uenaka and Marius Wernig of Stanford University; Jeffrey R. Jones, Ryan Goodman, Traci Newmeyer, Kelly Heard, Austin Kang and Fred H. Gage of The Salk Institute for Biological Studies; Yuki Sugiura and Makoto Suematsu from Keio University; Ling Liu and Joshua D. Rabinowitz of Princeton University; Erik M. Ullian of the University of California San Francisco; Geidy E. Serrano and Thomas G. Beach of the Banner Sun Health Research Institute.

The Howard Hughes Medical Institute Hanna H. Gray Fellows Program Faculty Phase and the Burroughs Welcome Fund PDEP Transition to Faculty funded the Penn State aspects of this work.