IDO1 inhibitors, drugs originally aimed at cancer, show potential in treating Alzheimer’s by improving brain metabolism. This could lead to therapies that not only manage but potentially reverse aspects of neurodegenerative diseases.
Cancer Drugs and Alzheimer’s Research
According to a recent study by researchers at Penn State, Stanford University, and an international team of collaborators, a type of drug that was developed for treating cancer holds promise as a new treatment for neurodegenerative diseases such as Alzheimer’s.
The scientists discovered 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 (Aug. 22) in the journal Science, suggest that IDO1 inhibitors currently being developed as a treatment 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 the chronic conditions that lack preventative treatments.
IDO1 Inhibitors: A New Hope for Neurodegenerative Diseases
“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,” said Melanie McReynolds, the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State and co-author on the paper. “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 the most common type of dementia, an umbrella term that refers to all age-associated neurodegenerative disorders, McReynolds explained. In 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.
Targeting Brain Metabolism to Combat Alzheimer’s
“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, the Edward F. and Irene Pimley Professor of Neurology and Neurological Sciences at the Stanford University School of Medicine and the study’s senior author.
Alzheimer’s disease affects the parts of the brain that control thought, memory and language, the result of progressive and irreversible loss of synapses and neural circuitry. As the disease progresses, symptoms can increase from mild memory loss to losing the ability to communicate and respond to the environment. Current treatments for the disease are focused on managing symptoms and slowing progression, through targeting the build-up of amyloid and tau plaques in the brain, but there are no approved treatments for combating the onset of the disease, McReynolds said.
Novel Approaches in Alzheimer’s Research Using IDO1 Inhibition
“Scientists have been targeting the downstream effects of what we identify as an issue with the way the brain powers itself,” said Praveena Prasad, doctoral student at Penn State and co-author on the paper. “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.”
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 stopping IDO1 helps restore healthy glucose metabolism in astrocytes, the star-shaped brain cells that provide metabolic support to neurons.
Exploring Metabolic Interventions for Neurodegenerative Conditions
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 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 that was required to power neurons. With IDO1 suppressed, metabolic support for neurons increased and restored their ability to function.
The researchers conducted the study in several 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 disease dementia as well as the broad spectrum of progressive neurodegenerative disorders known as tauopathies, explained Paras Minhas, current resident at Memorial Sloan Kettering Cancer Center who earned a combined medical and doctoral degree in neuroscience at Stanford School of Medicine and is first author on the paper
“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 visualize precisely how the brain’s metabolism is impacted with neurodegeneration.”
For more on this research, see Stanford Reverses Cognitive Decline in Alzheimer’s With Brain Metabolism Drug.
Reference: “Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies” by Paras S. Minhas, Jeffrey R. Jones, Amira Latif-Hernandez, Yuki Sugiura, Aarooran S. Durairaj, Qian Wang, Siddhita D. Mhatre, Takeshi Uenaka, Joshua Crapser, Travis Conley, Hannah Ennerfelt, Yoo Jin Jung, Ling Liu, Praveena Prasad, Brenita C. Jenkins, Yeonglong Albert Ay, Matthew Matrongolo, Ryan Goodman, Traci Newmeyer, Kelly Heard, Austin Kang, Edward N. Wilson, Tao Yang, Erik M. Ullian, Geidy E. Serrano, Thomas G. Beach, Marius Wernig, Joshua D. Rabinowitz, Makoto Suematsu, Frank M. Longo, Melanie R. McReynolds, Fred H. Gage and Katrin I. Andreasson, 23 August 2024, Science.
DOI: 10.1126/science.abm6131
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 of 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.
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6 Comments
“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.” But the answer is not a drug to poison the nerves. It’s changing your sleep position.
I am a medical anthropologist researcher and author, and have conducted research into sleep position and its impact on the brain and body. The greatest cause of reduced glucose metabolism in the brain is sleeping too flat, which reduces brain circulation, as many studies have shown. Gravity is essential for proper brain circulation, and head-of-bed elevation of 10-30 degrees is known to improve brain circulation. If the head is too flat all night, the circulation to and from the brain is sluggish, and the brain uses up much of its glucose and oxygen, and accumulated metabolic waste products. The glymphatic system, which is the lymphatic system in the brain and is part of the waste disposal and immune system, cannot drain the brain without gravity assistance, either. This means that sleeping too flat each night progressively pressurizes, congests, and toxifies the brain, and starves the brain of nutrients.
Of course, you can’t study this in tissue culture or mice. You need to study human disease within the context of human behavior and culture, and our culture encourages sleeping flat for long hours daily.
This sleep position issue helps explain why people get dementia, stroke, sleep apnea, glaucoma, migraines, and more. Strokes, for example, are known to happen in the middle of the night (mostly around 4am, in fact) after a night of excessive brain pressure, which can burst a blood vessel.
The brain is the central nervous system, influencing all bodily functions. If you deprive the brain of proper circulation by sleeping too flat, then you are asking for a host of problems that the medical industry will consider mysteries, since they don’t consider sleep position. Of course, Space Medicine knows about this, since zero gravity in space results in fluid shifting to the head and brain, causing many of these problems for astronauts. NASA studies zero gravity on Earth by having people lie flat, since the head and heart are on the same plane. (When standing, gravity helps pull blood from the head to the heart, and resists blood going to the head. When lying down, this gravity effect is lost, resulting in excessive brain pressure and reduced brain circulation.)
Everyone needs to try a personal “self study” of raising the head of your bed to see the change in the way they feel in the morning. People who try this report amazing, life-changing results. You will get results the very next day. There are many ways to do this that are easy, and cost-free.
With a family history of very, very mild food allergy reactions (which mainstream medicine still fails to recognize and/or research as true allergies; Dr. Arthur F. Coca, by 1935) and premature mortality due to complications of dementia under doctor’s care, as a now eighty year old lay male with documented multiple nearly subclinical non-IgE-mediated food and toxic food additive allergies, who is still living independently in a four season location, I cannot dispute Mr. Singer’s findings. But, I can add to them with personal experience convincing me that the underlying cause is allergy and toxic food additive ignorant and incompetent medical professionals and public officials, who fail to properly address what is cheaply and easily prevented (e.g., myself, albeit too late learned to save some family). All it takes is allergen identification with partial avoidance and natural, pure and safe diet. With the obesity epidemic being concurrent with the Alzheimer’s epidemic, it should be obvious to any reasonably prudent adult reading the article that glucose is a factor in both. Having lost close family to late stage dementia, if a repurposed anti-cancer drug was available then I would have wanted it tried. However, late stage treatment is no substitute for prevention. And, if elevating one’s head while sleeping can delay disability due to cognitive decline while still ingesting allergenic and officially approved toxic pseudo-foods, why not?
I agree, Charles, that food additives and allergies are a contributor to many problems. Many health problems are multifactorial. Many are biochemical, as you emphasize, but many are also biomechanical, which is my specialty. In this case, it’s about the physics of gravity; in other cases I have focused on the mechanical impact of tight clothing on circulation. Both are simple physics principles applied to the body, but ignored by medicine. If it doesn’t result in a drug being prescribed, medicine isn’t interested. And when you drug side-effects, and consider the immune-sensitizing effects of vaccinations, which can create food allergies and other autoimmune responses, medicine is often the cause.
Here’s a new treatment for you: meat.
What animals eat the plants and then you eat the animals.
Wow, what a revolutionary concept that is!
It’s what people did before we started agriculture and the fossil record indicates they had none of the chronic diseases that we have today.
Everything old is New again.
No soft tissues were preserved from the fossil remains. The fossils were not examined by a doctor.
In the past, people lived to be 40 years old as isolated tribes.
Today, more people are living longer (80-90) than in the past.
Gee, you mean repurposed drugs are a thing? Like Ivermectin?