A newly researched cancer drug shows potential as a treatment for neurodegenerative diseases, including Alzheimer’s, as revealed by a team from Penn State, Stanford University, and international collaborators.
A newly researched cancer drug shows potential as a treatment for neurodegenerative diseases, including Alzheimer’s, as revealed by a team from Penn State, Stanford University, and international collaborators.
The researchers found that blocking an enzyme known as indoleamine-2,3-dioxygenase 1 (IDO1) could help improve memory and brain function in models that simulate Alzheimer’s disease. This significant study, published on August 22 in the journal Science, proposes that IDO1 inhibitors, already being explored for various cancers like melanoma, leukemia, and breast cancer, might be repurposed to address the initial phases of neurodegenerative conditions, marking a groundbreaking development for chronic diseases that currently lack preventive treatments.
“Our findings highlight the great potential of IDO1 inhibitors, which are part of the drug arsenal being devised for cancer, to effectively target Alzheimer’s,” noted Melanie McReynolds, co-author and holder of the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State. “In the larger context of aging, cognitive decline is a major factor affecting the ability to age more healthily. Understanding and treating metabolic decline in neurological disorders could benefit not only those diagnosed but also families, society, and the economy as a whole.”
As the most common form of dementia, Alzheimer’s disease represents various age-related neurodegenerative disorders. According to the Centers for Disease Control and Prevention, about 6.7 million Americans were living with Alzheimer’s disease in 2023, with anticipations of its prevalence tripling by 2060.
“Inhibiting this enzyme, especially with agents that have been previously researched in human cancer trials, could advance our efforts to shield the brain from the damage incurred by aging and neurodegeneration,” stated Katrin Andreasson, senior author of the study and the Edward F. and Irene Pimley Professor of Neurology and Neurological Sciences at Stanford University School of Medicine.
Alzheimer’s affects brain areas responsible for thought, memory, and language, leading to progressive and irreversible loss of connections between neurons. As the disease progresses, individuals may experience a range of symptoms from minor memory lapses to severe communication breakdowns. Current therapies focus on alleviating symptoms and slowing disease progression through targeting amyloid and tau plaque build-ups, though no approved methods exist for preventing the onset of the disease, according to McReynolds.
“Researchers have primarily been addressing the secondary effects of the identified issues in brain function and energy,” said Praveena Prasad, a doctoral student at Penn State and co-author. “The treatments available seek to remove peptides that likely result from a larger underlying problem we could address before plaque formation occurs. Our findings show that by focusing on brain metabolism, we can not only slow but potentially reverse the disease’s progression.”
Using preclinical models including in vitro cellular models with amyloid and tau proteins, in vivo mouse models, and human cells from Alzheimer’s patients, the team demonstrated that inhibiting IDO1 improved healthy glucose metabolism in astrocytes—star-shaped brain cells that provide metabolic support to neurons.
IDO1 is an enzyme that breaks down tryptophan into kynurenine, initiating a reaction called the kynurenine pathway (KP), which is crucial for energy supply to brain cells. The researchers noted that excessive kynurenine production by IDO1 impaired glucose metabolism, necessary for neuronal energy. By inhibiting IDO1, they observed enhanced metabolic support for neurons, thereby restoring their functionality.
The study examined various Alzheimer’s disease models characterized by amyloid or tau build-up and found that blocking IDO1 affected both types. Their results imply that IDO1 may also play a role in other pathologies, like Parkinson’s disease dementia, as well as a range of other progressive neurodegenerative illnesses known as tauopathies, explained Paras Minhas, first author of the study and a resident at Memorial Sloan Kettering Cancer Center, who earned his medical and doctoral degrees in neuroscience from Stanford School of Medicine.
“The brain relies heavily on glucose for various functions, thus losing its capability to utilize glucose efficiently for energy can lead to metabolic and cognitive decline,” said Minhas. “This collaboration allowed us to visualize how neurodegeneration affects the brain’s metabolism.”
Additional authors from Penn State include lab manager Brenita Jenkins. The co-authors comprise 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 from Stanford University; Jeffrey R. Jones, Ryan Goodman, Traci Newmeyer, Kelly Heard, Austin Kang, and Fred H. Gage from The Salk Institute for Biological Studies; Yuki Sugiura and Makoto Suematsu from Keio University; Ling Liu and Joshua D. Rabinowitz from Princeton University; Erik M. Ullian from the University of California San Francisco; Geidy E. Serrano and Thomas G. Beach from the Banner Sun Health Research Institute.
This research received funding from the Howard Hughes Medical Institute Hanna H. Gray Fellows Program Faculty Phase and the Burroughs Welcome Fund PDEP Transition to Faculty, covering the Penn State contributions to the work.
