Neuroscientists at Stanford have linked Alzheimer’s disease to the disruption of brain metabolism via the kynurenine pathway, which is affected by amyloid plaque and tau proteins.
Their research has demonstrated that drugs blocking this pathway can restore cognitive function in Alzheimer’s mice by improving brain metabolism. This discovery not only bridges the gap between neuroscience and oncology but also provides a fast track to repurposing existing drugs for Alzheimer’s treatment.
Alzheimer’s Disease and Brain Energy Metabolism
Neuroscientists believe one of the key mechanisms by which Alzheimer’s disease impairs brain function is through the disruption of glucose metabolism, which is essential for energizing a healthy brain. Essentially, a decrease in metabolism deprives the brain of vital energy, thereby hindering cognitive functions and memory.
Against that backdrop, a team of neuroscientists at the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute have zeroed in on a critical regulator of brain metabolism known as the kynurenine pathway. They hypothesize that the kynurenine pathway is overactivated as a result of amyloid plaque and tau proteins that accumulate in the brains of patients with Alzheimer’s disease.
Restoring Cognitive Function in Lab Mice
Now, with support from research and training grants from the Knight Initiative, they have shown that by blocking the kynurenine pathway in lab mice with Alzheimer’s Disease, they can improve, or even restore, cognitive function by reinstating healthy brain metabolism.
“We were surprised that these metabolic improvements were so effective at not just preserving healthy synapses, but in actually rescuing behavior. The mice performed better in cognitive and memory tests when we gave them drugs that block the kynurenine pathway,” said senior author, Katrin Andreasson, a neurologist at the Stanford School of Medicine and member of the Wu Tsai Neurosciences Institute.
The study, which included collaborations with researchers at the Salk Institute for Biological Studies, Penn State University, and others, was published on August 22, 2024, in the journal Science.
Hungry Neurons
In the brain, kynurenine regulates production of the energy molecule lactate, which nourishes the brain’s neurons and helps maintain healthy synapses. Andreasson and her fellow researchers specifically looked at the enzyme indoleamine-2,3-dioxygenase 1 — or IDO1, for short — which generates kynurenine. Their hypothesis was that increases in IDO1 and kynurenine triggered by accumulation of amyloid and tau proteins would disrupt healthy brain metabolism and lead to cognitive decline.
“The kynurenine pathway is over activated in astrocytes, a critical cell type that metabolically supports neurons. When this happens, astrocytes cannot produce enough lactate as an energy source for neurons, and this disrupts healthy brain metabolism and harms synapses” Andreasson said. Blocking production of kynurenine by blocking IDO1 restores the ability of astrocytes to nourish neurons with lactate.
Potential Fast-Tracking of IDO1 Inhibitors
Best of all for Andreasson, and for Alzheimer’s patients, IDO1 is well known in oncology and there are already drugs in clinical trials to suppress IDO1 activity and production of kynurenine. That meant Andreasson could circumvent the time-intensive work of identifying new drugs and to begin testing in lab mice almost immediately.
In those tests, in which mice with Alzheimer’s Disease must navigate an obstacle course before and after drug intervention, Andreasson and team found that the drugs improved hippocampal glucose metabolism, corrected deficient astrocytic performance, and improved the mice’s spatial memory.
Promising Results Across Different Pathologies
“We also can’t overlook the fact that we saw this improvement in brain plasticity in mice with both amyloid and tau mice models. These are completely different pathologies, and the drugs appear to work for both,” Andreasson noted. “That was really exciting to us.”
Better yet, this intersection between neuroscience, oncology, and pharmacology could help speed drugs to market if proved effective in ongoing human clinical trials for cancer.
“We’re hopeful that IDO1 inhibitors developed for cancer could be repurposed for treatment of AD,” Andreasson stressed.
A Glimpse into the Future of Alzheimer’s Treatment
The next step is to test IDO1 inhibitors in human Alzheimer’s patients to see if they show similar improvements in cognition and memory. Prior clinical tests in cancer patients tested the effectiveness of IDO1 inhibitors on cancer but did not anticipate or measure improvements in cognition and memory. Andreasson is hoping to investigate IDO1 inhibitors in human trials for Alzheimer’s disease in the near future.
Reference: “Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies” 22 August 2024, Science.
DOI: 10.1126/science.abm6131
Stanford Wu Tsai Neurosciences Institute / Knight Initiative for Brain Resilience Authors:
Paras S. Minhas (co-lead), Amira Latif-Hernandez (co-lead), Aarooran S. Durairaj, Qian Wang, Siddhita D. Mhatre, Takeshi Uenaka, Joshua Crapser, Travis Conley, Hannah Ennerfelt, Yoo Jin Jung, Yeonglong Albert Ay, Matthew Matrongolo, Edward N. Wilson, Tao Yang, Marius Wernig, Frank M. Longo, and Katrin I. Andreasson (corresponding).
Other Contributing Institutions
The Salk Institute for Biological Studies (including co-lead author Jeffrey R. Jones), Keio University, Princeton University, Penn State University, UC San Francisco, and the Banner Sun Research Institute.
Wu Tsai Neurosciences Institute / Knight Initiative for Brain Resilience Support:
The research was supported by an Innovation Award and a Brain Resilience Scholar Award from the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute. The study made use of Wu Tsai Neurosciences Institute Community Laboratories: the Stanford Behavioral and Functional Neuroscience Laboratory and the Stanford Neuroscience Microscopy Service, as well as the Stanford Mass Spectroscopy Core.
Competing Interests:
Andreasson is a co-founder, board member, and consultant for Willow Neuroscience, Inc. Longo is a founder of, board member of, and consultant for and has financial interest in PharmatrophiX, a company focused on small-molecule development for treatment of neurodegenerative disorders.
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