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UNIVERSITY PARK, Pa. — In a scientific twist of good fortune, researchers have found that the path to treating Alzheimer’s disease may have been hiding in plain sight – by treating cancer. A class of drugs originally developed to combat cancer could unexpectedly revolutionize our approach to neurodegenerative disorders.
At the heart of this revolutionary discovery is an enzyme called indoleamine-2,3-dioxygenase 1, or IDO1 for short. This enzyme, which plays a role in breaking down the amino acid tryptophan (yes, the same one that makes you sleepy after Thanksgiving turkey), has been found to be a key player in the metabolic changes seen in Alzheimer’s disease.
The study, published in Science and led by Dr. Katrin Andreasson from Stanford University, builds upon previous research that identified a decrease in brain energy metabolism as a hallmark of Alzheimer’s disease. However, this new research goes a step further, uncovering the mechanism behind this energy deficit and proposing a novel solution.
“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,” says Melanie McReynolds, co-author of the study and the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State, in a media release.
The researchers found that increased activity of IDO1 in brain cells called astrocytes leads to a buildup of a compound called kynurenine. This buildup disrupts the normal energy production process in these cells, ultimately starving neurons of a vital energy source called lactate.
To test their theory, the team used a multi-pronged approach. They examined brain tissue from people with different stages of Alzheimer’s disease, studied mice genetically engineered to develop Alzheimer’s-like symptoms, and even created human brain cells in the lab from stem cells of people with and without the disease.
In all these models, they found evidence of increased IDO1 activity and its negative effects on brain energy metabolism. The exciting part? When they used a drug to block IDO1 activity, they saw improvements in brain energy metabolism, memory, and cognitive function in the Alzheimer’s mouse models.
“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,” notes Dr. Andreasson.
The drug used in the study, called PF06840003, is particularly promising because it can cross the blood-brain barrier, a protective shield that prevents many substances from entering the brain. This means the drug could potentially be given orally and still reach its target in the brain.
Perhaps most intriguingly, the study found that this approach was effective not just in models of the more common form of Alzheimer’s (which involves the buildup of a protein called amyloid-beta) but also in a model of a related condition involving the accumulation of a protein called tau. This suggests that the IDO1-kynurenine pathway might be a common factor in different types of neurodegenerative diseases.
“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,” explains Praveena Prasad, a doctoral student at Penn State and co-author on the paper.
While these results are extremely promising, it’s important to note that successful treatments in mouse models don’t always translate to humans. However, the fact that the researchers also saw similar effects in human brain cells grown in the lab provides additional support for this approach.
This study represents a significant shift in how we think about Alzheimer’s disease. Instead of focusing solely on the buildup of abnormal proteins in the brain, it suggests that restoring normal energy metabolism could be a powerful way to combat the disease. If these findings hold up in human trials, it could lead to a new class of treatments for Alzheimer’s and potentially other neurodegenerative diseases, offering hope to millions of people worldwide.
Paper Summary
Methodology
The researchers employed a comprehensive approach to investigate the role of IDO1 in Alzheimer’s disease. They began by examining brain tissue from individuals at various stages of AD to measure kynurenine and related substance levels. To test the effects of blocking IDO1, they utilized three different types of genetically engineered mice that develop AD-like symptoms. The team also created human brain cells, including neurons and astrocytes, in the laboratory from stem cells of people with and without AD.
A drug called PF06840003 was used to block IDO1 activity in both the mouse models and lab-grown human cells. The mice’s memory and cognitive abilities were assessed using maze tests. Finally, the researchers employed advanced techniques to track glucose metabolism in the brain, including injecting labeled glucose and using mass spectrometry to observe its utilization.
Key Results
The study yielded several significant findings. IDO1 activity and kynurenine levels were found to be higher in the brain tissue of people with AD compared to those without the disease. When IDO1 was blocked in mouse models of AD, the animals showed improved performance on memory tests.
This blockade also restored normal glucose metabolism in the hippocampus of AD mouse models. Interestingly, lab-grown human astrocytes from people with AD exhibited abnormal metabolism, which was corrected by blocking IDO1. Importantly, these effects were observed in models of both amyloid-beta and tau pathology, suggesting a common mechanism underlying different forms of the disease.
Study Limitations
While the study’s findings are promising, there are several limitations to consider. The main results come from mouse models, which don’t always translate directly to humans, despite the study’s use of multiple models, including human cells. The research focused on specific types of cells (astrocytes and neurons) and may not capture the full complexity of the human brain.
Additionally, the long-term effects and potential side effects of blocking IDO1 in humans remain unknown. The study also didn’t explore how this approach might interact with other potential AD treatments, which could be an important consideration for future research.
Discussion & Takeaways
This study proposes a novel approach to understanding and treating Alzheimer’s disease by focusing on energy metabolism rather than solely on protein buildup. The research suggests that increased IDO1 activity in astrocytes may contribute to the energy deficit observed in AD brains. By blocking IDO1, it appears possible to restore normal energy metabolism and improve cognitive function in AD models.
Importantly, this approach could potentially work for different types of neurodegenerative diseases. The study highlights that restoring normal brain metabolism could be a powerful way to combat AD, possibly in combination with other treatments. If these results are confirmed in human trials, it could lead to the development of a new class of AD treatments, offering hope to millions affected by this devastating disease.
Funding & Disclosures
The study received funding from various organizations, including the National Institutes of Health, the American Heart Foundation, and several private foundations. The Penn State aspects of this work were supported by the Howard Hughes Medical Institute Hanna H. Gray Fellows Program Faculty Phase and the Burroughs Welcome Fund PDEP Transition to Faculty.
In the interest of transparency, some of the authors disclosed financial interests: one is a co-founder and consultant for a neuroscience company, while another is a founder and consultant for a company developing treatments for neurodegenerative disorders. These disclosures are crucial for readers to consider potential conflicts of interest when interpreting the study’s findings. are important for transparency and to allow readers to consider potential conflicts of interest.
