Study shows: Cancer drug could treat early-stage Alzheimer's

A drug developed to treat cancer shows promise for new treatments for neurodegenerative diseases such as Alzheimer's. This is the result of a recent study by researchers from Pennsylvania State University, Stanford University and an international team.

The researchers discovered that by blocking a specific enzyme called indoleamine 2,3-dioxygenase 1, or IDO1, they could rescue memory and brain function in models that mimic Alzheimer's disease.

The results published in the journal Science, suggest that IDO1 inhibitors, currently being developed as treatments for many cancers, including melanoma, leukemia and breast cancer, could also be used to treat the early stages of neurodegenerative diseases – a first for chronic conditions for which there is no preventive treatment.

“We show that IDO1 inhibitors, which are already part of the repertoire of drugs developed for cancer treatment, have high potential for the targeted treatment of Alzheimer's disease,” said Melanie McReynolds, holder of the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State and co-author of the article.

“In the broader context of aging, neurological decline is one of the biggest cofactors that contribute to the inability to age healthily. The benefits of understanding and treating metabolic decline in neurological diseases will impact not only those affected, but also our families, our society and our entire economy.”

Alzheimer's disease is the most common form of dementia, an umbrella term that encompasses all age-related neurodegenerative diseases, McReynolds explained. By 2023, as many as 6.7 million Americans will be living with Alzheimer's, according to the Centers for Disease Control and Prevention, and the prevalence is expected to triple by 2060.

“Inhibiting this enzyme, especially with compounds previously studied in human clinical trials against cancer, could be a major advance in finding ways to protect our brains from the damage caused by aging and neurodegeneration,” said Katrin Andreasson, 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 affects the parts of the brain that control thinking, memory and language. It is the result of a progressive and irreversible loss of synapses and neural circuits.

As the disease progresses, symptoms may worsen, ranging from mild memory loss to loss of the ability to communicate and respond to the environment.

Current treatments focus on relieving symptoms and slowing the progression of the disease by targeting the buildup of amyloid and tau plaques in the brain. However, there are no approved treatments to combat the onset of the disease, McReynolds said.

“The scientists focused on the knock-on effects of what we identified as a problem with the brain's energy supply,” said Praveena Prasad, a doctoral student at Pennsylvania State University and co-author of the study.

“Currently available therapies aim to remove peptides that are likely the result of a larger problem that we can attack before those peptides can form plaques. We show that by targeting brain metabolism, we can not only slow the progression of this disease, but reverse it.”

Using preclinical models – in vitro cell models with amyloid and tau proteins, in vivo mouse models and in vitro human cells from Alzheimer's patients – the researchers were able to demonstrate that stopping IDO1 helps restore healthy glucose metabolism in astrocytes, star-shaped brain cells that support neurons with their 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 critical role in how the body supplies the brain with cellular energy. The researchers found that when IDO1 produced too much kynurenine, it reduced glucose metabolism in astrocytes, which was needed to power neurons. When IDO1 was suppressed, metabolic support to neurons increased and their functionality was restored.

The researchers conducted the study on several models of Alzheimer's pathology, namely amyloid and tau accumulation, respectively, and found that the protective effect of blocking IDO1 affects these two different pathologies.

Their results suggest that IDO1 may also be relevant in diseases with other pathological manifestations, such as Parkinson's dementia and the broad spectrum of progressive neurodegenerative diseases known as tauopathies, explained Paras Minhas, currently a resident at Memorial Sloan Kettering Cancer Center, who earned a combined medical and doctoral degree in neuroscience from the Stanford School of Medicine and is the study's lead author.

“The brain is highly dependent on glucose to supply energy for many processes. Losing the ability to use glucose effectively for metabolism and energy production can therefore trigger a metabolic decline and, in particular, a decline in cognitive abilities,” said Minhas.

“Through this collaboration, we were able to visualize exactly how brain metabolism is affected by neurodegeneration.”