Kynurenine pathway blockade shows promise for restoring brain metabolism in Alzheimer’s

One of the many ways neuroscientists think Alzheimer’s disease can take away brain function is by disrupting the glucose metabolism needed to fuel the healthy brain. Essentially, a declining metabolism robs the brain of energy, impairing thinking and memory.

Against that backdrop, a team of neuroscientists from the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute has focused on a critical regulator of brain metabolism known as the kynurenine pathway. They hypothesize that the kynurenine pathway is overactive due to amyloid plaque and tau proteins that build up in the brains of Alzheimer’s disease patients.

Now, with support from research and training grants from the Knight Initiative, they have shown that by blocking the kynurenine pathway in laboratory mice with Alzheimer’s disease, they can improve or even restore cognitive function by restoring healthy brain metabolism.

We were surprised that these metabolic improvements were so effective not only in maintaining healthy synapses, but actually to rescue behavior. The mice performed better in cognitive and memory tests when we gave them drugs that block the kynurenine pathway.”

Katrin Andreasson, senior author, neurologist at 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, appeared Aug. 22, 2024, in the journal Science.

Hungry neurons

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 her fellow researchers looked specifically at the enzyme indoleamine-2,3-dioxygenase 1-; or IDO1, simply -; that generates kynurenine. Their hypothesis was that increases in IDO1 and kynurenine caused by accumulation of amyloid and tau proteins would disrupt healthy brain metabolism and lead to cognitive decline.

“The kynurenine pathway is overactivated 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 damages synapses,” Andreasson said. Blocking kynurenine production by blocking IDO1 restores the ability of astrocytes to supply neurons with lactate.

Best of all for Andreasson, and for the patients with Alzheimer’s disease, IDO1 is well known in oncology and there are already drugs in clinical trials to suppress IDO1 activity and kynurenine production. That meant Andreasson could bypass the time-consuming work of identifying new drugs and start testing on laboratory mice almost immediately.

In those tests, in which mice with Alzheimer’s disease had to navigate an obstacle course before and after drug intervention, Andreasson and team found that the drugs improved glucose metabolism in the hippocampus, corrected defective astrocytic performance and improved the mice’s spatial memory.

Promise kept

“We also can’t ignore the fact that we saw this improvement in brain plasticity in both amyloid and tau mouse models. These are completely different pathologies, and the drugs seem to work for both,” Andreasson noted . “That was very exciting for us.”

Better yet, this intersection between neuroscience, oncology and pharmacology could help drugs get to market faster if they prove effective in ongoing human cancer clinical trials.

“We are hopeful that IDO1 inhibitors developed for cancer can be repurposed for the treatment of AD,” Andreasson emphasized.

The next step is to test IDO1 inhibitors in human Alzheimer’s patients to see if they show similar improvements in cognition and memory. Preliminary clinical trials in cancer patients tested the effectiveness of IDO1 inhibitors on cancer, but did not anticipate or measure improvements in cognition and memory. Andreasson hopes to investigate IDO1 inhibitors in human trials of Alzheimer’s disease in the near future.