SUMMARY: Inhibiting the kynurenine pathway, which controls brain metabolism, can restore cognitive function in laboratory mice with Alzheimer’s disease, a condition in which the pathway is overactive, inhibiting glucose metabolism and starving neurons of energy.
By blocking this pathway, the researchers were able to improve memory and brain plasticity in mice, offering hope for new therapies for humans: IDO1 inhibitors, currently in clinical trials for cancer, could potentially be repurposed to treat Alzheimer’s disease.
Key Facts:
Inhibiting the kynurenine pathway in mice with Alzheimer’s disease restored brain metabolism and improved memory. In Alzheimer’s disease, the kynurenine pathway is overactive and inhibits glucose metabolism in the brain. Drugs that target this pathway, originally developed for cancer treatment, are promising for treating Alzheimer’s disease.
Source: Stanford
Neuroscientists believe that one of the many ways Alzheimer’s disease robs the brain of function is by disrupting glucose metabolism, which provides energy to a healthy brain. Essentially, slowed metabolism robs the brain of energy, impairing thinking and memory.
Against this backdrop, a team of neuroscientists from the Knight Brain Resilience Initiative at Stanford University’s Wu Tsai Neuroscience Institute zeroed in on a key regulator of brain metabolism known as the kynurenine pathway.
They hypothesize that the kynurenine pathway becomes overactivated as a result of amyloid plaques and tau protein that accumulate in the brains of people with Alzheimer’s disease.
Now, with support from a Knight Initiative Research and Training grant, researchers have demonstrated that by inhibiting the kynurenine pathway in lab mice with Alzheimer’s disease, they can restore healthy brain metabolism and improve or even reverse cognitive function.
“We were surprised to see that improving metabolism was so effective not only in maintaining healthy synapses but actually restoring behavior. When we gave mice a drug that inhibited the kynurenine pathway, they performed better on cognitive and memory tests,” said lead author Katrin Andreasson, a neuroscientist at the Stanford University School of Medicine and a member of the Wu Tsai Neuroscience Institute.
This research was conducted in collaboration with researchers from the Salk Institute for Biological Studies, Pennsylvania State University, and others, and was published in Science on August 22, 2024.
Starving Neurons
In the brain, kynurenine controls the production of the energy molecule lactate, which nourishes the brain’s neurons and helps maintain healthy synapses. Andreasson and her colleagues focused specifically on the enzyme that produces kynurenine, indoleamine-2,3-dioxygenase 1 (IDO1 for short).
Their hypothesis was that increases in IDO1 and kynurenine, caused by the accumulation of amyloid and tau proteins, interfere with healthy brain metabolism, leading to cognitive decline.
“The kynurenine pathway becomes overactive in astrocytes, a key cell type that provides metabolic support to neurons. When this happens, astrocytes cannot produce enough lactate as an energy source for neurons, which interferes with healthy brain metabolism and harms synapses,” Andreasson said.
Blocking kynurenine production by inhibiting IDO1 restores the ability of astrocytes to nourish neurons with lactate.
Best of all for Andreasson and Alzheimer’s patients, IDO1 is well known in oncology, and drugs that inhibit IDO1 activity and kynurenine production are already in clinical trials, meaning Andreasson can avoid the time-consuming task of identifying new drugs and begin testing them in lab mice almost immediately.
By testing mice with Alzheimer’s disease through an obstacle course before and after the drug intervention, Andreasson and his team found that the drug improved glucose metabolism in the hippocampus, corrected astrocyte dysfunction, and improved the mice’s spatial memory.
A promise kept
“What’s also exciting for us is the fact that we saw improvements in mouse brain plasticity in both mouse models of amyloid and tau. These are completely different disease conditions, but the drug seems to work in both,” Andreasson said.
Even better, this intersection of neuroscience, oncology, and pharmacology could help speed the drug to market if it proves effective in ongoing cancer clinical trials.
“We hope that IDO1 inhibitors developed for cancer treatment can be repurposed to treat AD,” Andreasson emphasized.
The next step is to test IDO1 inhibitors in human Alzheimer’s patients to see if they produce similar improvements in cognition and memory. Previous clinical trials in cancer patients have tested the effectiveness of IDO1 inhibitors against cancer, but have not predicted or measured improvements in cognition and memory. Andreasson hopes to investigate IDO1 inhibitors in human clinical trials for Alzheimer’s in the near future.
Alzheimer’s and memory research news
Author: Nicholas Wyler
Source: Stanford
Contact: Nicholas Weiler – Stamford
Image: This image is provided by Neuroscience News
Original research: Closed access.
“Restoring glucose metabolism in the hippocampus restores cognition across the spectrum of Alzheimer’s disease pathology” by Katrin Andreasson et al., Science
Abstract
Restoring hippocampal glucose metabolism rescues cognitive performance across the spectrum of Alzheimer’s disease pathology
introduction
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive and irreversible loss of synapses and neural circuits. Key pathophysiological processes that contribute to synapse loss, including disruption of proteostasis, accumulation of misfolded amyloid and tau, and microglial dysfunction, are being intensively studied with the goal of discovering disease-modifying therapies.
However, concomitant with these distinct pathologies is a persistent decline in glucose metabolism in the brain, and recent proteomics has revealed that astrocyte and microglial metabolism is severely impaired in AD patients.
basis
Astrocytes produce lactate, which is transported to neurons to drive mitochondrial respiration and support synaptic activity. Recent studies have implicated indoleamine-2,3-dioxygenase 1 (IDO1), an enzyme expressed in astrocytes, in multiple neurodegenerative diseases, including AD. IDO1 is the rate-limiting enzyme in the conversion of tryptophan (TRP) to kynurenine (KYN), a metabolite that causes immunosuppression in inflammatory and tumor settings through interaction with the aryl hydrocarbon receptor (AhR).
IDO1 activity is significantly upregulated by various immune stimuli, and in the brain, IDO1 is expressed in astrocytes and microglia, but not neurons, where levels can increase in response to inflammatory stimuli.
result
We report that inhibition of IDO1 and generation of KYN restores astrocytic metabolic support for neurons and restores hippocampal synaptic plasticity and memory function in preclinical models of amyloid and tau pathology Activation of astrocytic IDO1 by amyloid-β and tau oligomers, two major pathological effectors in AD, increases KYN and inhibits glycolysis in an AhR-dependent manner.
Conversely, pharmacological IDO1 inhibition restores astrocytic glycolysis and lactate production.In amyloid-producing APPSwe-PS1∆E9 and 5XFAD mice, as well as tau-producing P301S mice, IDO1 inhibition improves hippocampal glucose metabolism and restores spatial memory, as shown by metabolic and MALDI-MS (matrix-assisted laser desorption ionization mass spectrometry) analyses.
IDO1 inhibition restores hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner, suggesting that IDO1 activity inhibits astrocytes’ metabolic support of neurons. Indeed, in vitro mass labeling of human astrocytes demonstrates that IDO1 regulates lactate production by astrocytes, which is then taken up by human neurons.
In cocultures of astrocytes and neurons derived from AD patients, IDO1 inhibition corrected defects in astrocyte lactate production and migration into neurons and improved neuronal glucose metabolism.
Conclusion
In addition to uncovering a previously uncharacterized role for IDO1 in brain glucose metabolism, our study highlights the potential for brain-penetrant IDO1 inhibitors developed as adjuvant therapies for cancer to be repurposed for the treatment of neurodegenerative diseases such as AD.
This study also uncovers a common mechanism contributing to neuronal dysfunction across different pathologies: in addition to AD, manipulation of IDO1 may also be relevant to Parkinson’s disease dementia, characterized by amyloid accumulation in addition to α-synuclein, as well as a wide range of tauopathies.
Dysfunction in astrocytic glucose metabolism may also contribute to other neurodegenerative diseases characterized by the accumulation of other misfolded proteins, in which increased kynurenine pathway metabolites have been observed.
