The results of research in mice suggest that a type of drug developed for treating cancer may hold promise as a new treatment for neurodegenerative disorders such as Alzheimer’s disease (AD).
The studies, by scientists at Pennsylvania State University, Stanford University and an international team of collaborators, found that blocking an enzyme called indoleamine-2,3-dioxygenase 1 (IDO1) in mouse models of AD restored metabolism in brain astrocytes, and rescued memory and brain function. The findings suggest that IDO1 inhibitors currently being developed as a treatment for different types of cancer—including melanoma, leukemia and breast cancer—could be repurposed to treat the early stages of AD and potentially other neurodegenerative diseases, which would be a first for the chronic conditions that lack preventative treatments.
“Inhibiting this enzyme, particularly with compounds that have been previously investigated in human clinical trials for cancer, could be a big step forward in finding ways to protect our brains from the damage caused by aging and neurodegeneration,” said Katrin Andreasson, MD, the Edward F. and Irene Pimley Professor of Neurology and Neurological Sciences at the Stanford University School of Medicine.
“We’re showing that there is high potential for IDO1 inhibitors, which are already within the repertoire of drugs being developed for cancer treatments, to target and treat Alzheimer’s,” added Melanie McReynolds, PhD, the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State. “In the broader context of aging, neurological decline is one of the biggest co-factors of being unable to age healthier. The benefits of understanding and treating metabolic decline in neurological disorders will impact not just those who are diagnosed, but our families, our society, our entire economy.”
Alzheimer’s disease is an age-associated neurodegenerative disorders. CDC figures cited by the team indicate that in 2023, as many as 6.7 million Americans were living with Alzheimer’s disease, and prevalence of the disease is expected to triple by 2060.
Alzheimer’s disease affects the parts of the brain that control thought, memory and language, and is caused by progressive and irreversible loss of synapses and neural circuitry. As the disease progresses, symptoms can increase from mild memory deficits to losing the ability to communicate and respond to the environment. Current treatments for AD are focused on managing symptoms and slowing progression, through targeting the build-up of amyloid and tau plaques in the brain.
“Major pathophysiologic processes that contribute to synaptic loss, including disrupted proteostasis, accumulation of misfolded amyloid and tau, and microglial dysfunction, are being vigorously investigated with the goal of identifying disease-modifying therapies,” the team stated. However, there are no approved treatments for combating onset of the disease, explained co-author Melanie McReynolds, PhD, the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State.
Among the many ways neuroscientists think Alzheimer’s disease may strip away brain function is by disrupting the glucose metabolism needed to fuel the healthy brain. In essence, declining metabolism robs the brain of energy, impairing thinking and memory. “… coincident with these distinct pathologies is a sustained decline in cerebral glucose metabolism, with recent proteomics revealing a marked disruption of astrocytic and microglial metabolism in AD subjects,” the authors added. “Astrocytes generate lactate that is exported to neurons to fuel mitochondrial respiration and support synaptic activity.”
Against that backdrop, the researchers, including neuroscientists at the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute focused on the kynurenine pathway, a critical regulator of brain metabolism. The body’s production of kynurenine is the first part of a chain reaction that plays a critical role in how the body provides cellular energy to the brain.
In the brain, kynurenine regulates production of the energy molecule lactate, which nourishes the brain’s neurons and helps maintain healthy synapses. Andreasson and fellow researchers specifically looked at IDO1, which is the rate-limiting enzyme in the conversion of tryptophan (TRP) to kynurenine. Their hypothesis was that increases in IDO1 and kynurenine triggered by accumulation of amyloid and tau proteins would disrupt healthy brain metabolism and lead to cognitive decline.
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 inhibiting IDO1 helps restore healthy glucose metabolism in astrocytes, the star-shaped brain cells that provide metabolic support to neurons. Andreasson noted, “The kynurenine pathway is over activated in astrocytes, a critical cell type that metabolically supports neurons. When this happens, astrocytes cannot produce enough lactate as an energy source for neurons, and this disrupts healthy brain metabolism and harms synapses.”
IDO1 is well known in oncology and there are already drugs in clinical trials to suppress IDO1 activity and production of kynurenine. This allowed Andreasson to begin testing in lab mice almost immediately. From these experiment, in which mice with Alzheimer’s Disease must navigate an obstacle course before and after drug intervention, Andreasson and team found that the drugs improved hippocampal glucose metabolism, corrected deficient astrocytic performance, and improved the mice’s spatial memory. Blocking production of kynurenine by blocking IDO1 restored the ability of astrocytes to nourish neurons with lactate.
“The mice performed better in cognitive and memory tests when we gave them drugs that block the kynurenine pathway,” said Andreasson, a member of the Wu Tsai Neurosciences Institute. “We were surprised that these metabolic improvements were so effective at not just preserving healthy synapses, but in actually rescuing behavior.”
“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,” said first author Paras Minhas, MD, PhD, currently a resident at Memorial Sloan Kettering Cancer Center who earned a combined medical and doctoral degree in neuroscience at Stanford School of Medicine. “Through this collaboration we were able to visualize precisely how the brain’s metabolism is impacted with neurodegeneration.”
The researchers conducted the study in several models of Alzheimer’s pathology, including amyloid or tau accumulation, and found that the protective effects of blocking IDO1 cut across these two different pathologies. The findings suggest that IDO1 may be relevant in diseases with other types of pathology, such as Parkinson’s disease dementia, as well as the broad spectrum of progressive neurodegenerative disorders known as tauopathies.
“We also can’t overlook the fact that we saw this improvement in brain plasticity in mice with both amyloid and tau mice models,” Andreasson noted. “These are completely different pathologies, and the drugs appear to work for both. That was really exciting to us.” The authors further commented in their research summary, “There is the possibility that deficient astrocytic glucose metabolism could also underlie other neurodegenerative diseases characterized by the accumulation of other misfolded proteins where increases in kynurenine pathway metabolites have been observed.”
This intersection between neuroscience, oncology, and pharmacology could help speed drugs to market if proved effective in ongoing human clinical trials for cancer. “We’re hopeful that IDO1 inhibitors developed for cancer could be repurposed for treatment of AD,” Andreasson stressed. Added co-author Praveena Prasad, a doctoral student at Penn State, “Scientists have been targeting the downstream effects of what we identify as an issue with the way the brain powers itself … The therapies that are currently available are working to remove peptides that are likely the result of a bigger issue we can target before those peptides can start forming plaques. We’re demonstrating that by targeting the brain’s metabolism, we can not only slow, but reverse the progression of this disease.”
The next step is to test IDO1 inhibitors in human Alzheimer’s patients to see if they show similar improvements in cognition and memory. Prior clinical tests in cancer patients tested the effectiveness of IDO1 inhibitors on cancer but did not anticipate or measure improvements in cognition and memory. Andreasson is hoping to investigate IDO1 inhibitors in human trials for Alzheimer’s disease in the near future.
In a related perspective, Lance A. Johnson, PhD, and Shannon L. Macauley, PhD, at the University of Kentucky, Lexington, commented that the study by Andreasson et al shows how targeting key metabolic checkpoints in glia can “profoundly affect brain health” by restoring metabolic flexibility and cellular cooperation. “Borrowing lessons from cancer therapeutics, it can no longer be accepted that changes in metabolism are merely a by-product of AD pathology and neurodegeneration,” the perspective authors stated.
And while it will be necessary to study the role of the kynurenine pathway in modulating other cell types in the central nervous system, the newly reported study, “… adds to a growing body of literature showing that metabolic flux is a promising therapeutic target in AD.” Moreover, Johnson and Macauley noted, “… it will be interesting to see in future studies whether major risk factors, such as APOE and TREM2, similarly modulate the same TRP-KYN–HIF1a (hypoxia inducible factor 1a, a transcription factor) axis in glia.”
