Memory and brain function of Alzheimer mice “saved” by cancer drug

Results from studies in mice suggest that a type of drug developed to treat cancer may hold promise as a new treatment for neurodegenerative diseases such as Alzheimer's disease (AD).

The studies, conducted by scientists at Pennsylvania State University, Stanford University and an international team, 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 treatments for several cancers – including melanoma, leukemia and breast cancer – could be used to treat the early stages of AD and possibly other neurodegenerative diseases, a first for the chronic conditions for which there are no preventive treatments.

“Inhibiting this enzyme, especially with compounds previously studied in human clinical trials for cancer, could be a major advance in finding ways to protect our brains from damage caused by aging and neurodegeneration,” said Katrin Andreasson, MD, Edward F. and Irene Pimley Professor of Neurology and Neurological Sciences at Stanford University School of Medicine.

“We show that IDO1 inhibitors, already in the repertoire of drugs developed for cancer treatment, have high potential to target Alzheimer's disease,” added Melanie McReynolds, PhD, 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 largest cofactors that contribute to the inability to age healthily. The benefits of understanding and treating metabolic decline in neurological disease will impact not only those affected, but also our families, our society and our entire economy.”

Andreasson is lead author of the team’s published paper in Scienceentitled “Restoring hippocampal glucose metabolism rescues cognitive abilities in all Alzheimer's disease disorders.” In the report, the researchers concluded: “Our study not only uncovered the crucial role of IDO1 in brain glucose metabolism, but also highlighted the potential of IDO1 inhibitors, which were developed as adjunctive therapy for cancer and can now also be used for neurodegenerative diseases such as Alzheimer's.”

Alzheimer's is an age-related neurodegenerative disease. CDC figures cited by the team show that up to 6.7 million Americans will have Alzheimer's by 2023, and the 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 a progressive and irreversible loss of synapses and neural circuits. As the disease progresses, symptoms can progress from mild memory deficits to loss of the ability to communicate and respond to the environment. Current treatments for Alzheimer's focus on relieving symptoms and slowing progression by targeting the buildup of amyloid and tau plaques in the brain.

“Key pathophysiological processes that contribute to synapse loss, including impaired proteostasis, accumulation of misfolded amyloid and tau, and microglial dysfunction, are being intensively studied to find disease-modifying therapies,” the team explained. However, there are no approved treatments to combat the onset of the disease, explained co-author Melanie McReynolds, PhD, holder of the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State.

Neuroscientists believe that one way Alzheimer's can affect brain function is by disrupting the glucose metabolism needed to fuel the healthy brain. Essentially, the declining metabolism robs the brain of energy, impairing thinking and memory. “…coinciding with these different pathologies is a persistent decline in cerebral glucose metabolism, with recent proteomic studies showing a marked disruption of astrocytic and microglial metabolism in Alzheimer's patients,” the authors added. “Astrocytes generate lactate, which is exported to neurons to drive mitochondrial respiration and support synaptic activity.”

Against this background, the researchers, including neuroscientists from the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute at Stanford, focused on the Kynurenine pathway, a important regulator of brain metabolism. The body's production of kynurenine is the first step in a chain reaction that plays a crucial role in how the body supplies the brain with cellular energy.

In the brain, kynurenine regulates the production of the energy molecule lactate, which nourishes the brain's neurons and helps maintain healthy synapses. Andreasson and his colleagues specifically studied IDO1, the rate-limiting enzyme in the conversion of tryptophan (TRP) to kynurenine. They hypothesized that increases in IDO1 and kynurenine triggered by the accumulation of amyloid and tau proteins would disrupt healthy brain metabolism and lead to cognitive decline.

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 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 overactivated in astrocytes, an important cell type that provides metabolic support to neurons. When this happens, astrocytes cannot produce enough lactate as an energy source for neurons, disrupting healthy brain metabolism and damaging synapses.”

IDO1 is well known in oncology, and there are already drugs in clinical trials that suppress IDO1 activity and the production of kynurenine. This allowed Andreasson to begin testing in laboratory mice almost immediately. In these experiments, in which mice with Alzheimer's disease had to complete an obstacle course before and after drug treatment, Andreasson and his team found that the drugs improved glucose metabolism in the hippocampus, corrected the deficient performance of astrocytes, and improved the mice's spatial memory. Blocking kynurenine production by blocking IDO1 restored the astrocytes' ability to supply 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 not only so effective in maintaining healthy synapses, but actually rescue Behave.”

“The brain is highly 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 doctorate degree in neuroscience from Stanford School of Medicine. “Through this collaboration, we were able to visualize exactly how brain metabolism is affected by neurodegeneration.”

The researchers conducted the study on several models of Alzheimer's pathology, including amyloid or tau accumulation, and found that the protective effect of blocking IDO1 affects these two different pathologies. The results suggest that IDO1 may be relevant in diseases involving other types of pathology, such as Parkinson's dementia, as well as the broad spectrum of progressive neurodegenerative diseases known as tauopathies.

“We also cannot overlook the fact that we observed this improvement in brain plasticity in both amyloid and tau mice,” Andreasson noted. “These are completely different pathologies, and the drugs seem to work in both. That was really exciting for us.” The authors further commented in their research summary: “There is a possibility that defective astrocytic glucose metabolism may also underlie other neurodegenerative diseases characterized by the accumulation of other misfolded proteins in which an increase in kynurenine pathway metabolites has been observed.”

This intersection of neuroscience, oncology and pharmacology could help bring drugs to market faster if they prove effective in ongoing clinical trials against cancer. “We hope that IDO1 inhibitors developed for cancer can be used to treat Alzheimer's,” Andreasson emphasized. Co-author Praveena Prasad, a doctoral student at Penn State, added, “Scientists have focused on the knock-on effects of what we identified as a problem with the way the brain powers itself… The therapies currently available work to remove peptides that are likely the result of a larger problem that we can attack before those peptides can start to form plaques. We show that by targeting brain metabolism, we can not only slow the progression of this disease, but reverse it.”

The next step is to test IDO1 inhibitors in human Alzheimer's patients to see if they show similar improvements in cognition and memory. Previous clinical trials in cancer patients have tested the effectiveness of IDO1 inhibitors in cancer, but failed to predict or measure improvements in cognition and memory. Andreasson hopes to study IDO1 inhibitors in human trials for Alzheimer's in the near future.

In a related perspective, Lance A. Johnson, PhD, and Shannon L. Macauley, PhD, of the University of Kentucky, Lexington, commented that the study by Andreasson et al. shows how targeting key metabolic checkpoints in glial cells can “profoundly impact brain health” by restoring metabolic flexibility and cellular cooperation. “Given the experience of cancer therapy, one can no longer accept that changes in metabolism are merely a byproduct of AD pathology and neurodegeneration,” the perspective's authors explained.

And while it will be necessary to investigate the role of the kynurenine pathway in modulating other cell types in the central nervous system, the newly published study “…adds to a growing body of literature showing that metabolic flux is a promising therapeutic target in AD.” In addition, Johnson and Macauley noted, “…it will be interesting to see in future studies whether important risk factors such as APÖ And TREM2similarly modulate the same TRP-KYN–HIF1a (hypoxia-inducible factor 1a, a transcription factor) axis in glia.”