New discovery could boost brain metabolism and restore cognitive function in Alzheimer’s patients

Alzheimer’s disease may impair brain function by disrupting glucose metabolism, which is essential for brain energy. This energy depletion can significantly affect memory and cognitive abilities. Researchers at Stanford's Knight Initiative for Brain Resilience have focused on a key player in brain metabolism—the kynurenine pathway. They believe that this pathway becomes overactive due to the accumulation of amyloid plaques and tau proteins in the brains of Alzheimer’s patients.

Supported by grants from the Knight Initiative, these researchers discovered that blocking the kynurenine pathway in mice with Alzheimer’s could restore cognitive function by reviving healthy brain metabolism. This breakthrough suggests a potential new treatment approach for the disease.

Katrin Andreasson, a neurologist at Stanford and a senior author of the study, expressed her astonishment at the results. “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,” she said.

The study, involving collaborations with researchers from the Salk Institute for Biological Studies and Penn State University, was published in the journal Science.

The kynurenine pathway regulates the production of lactate, a crucial energy molecule that nourishes neurons and maintains synaptic health. The research team particularly examined the enzyme indoleamine-2,3-dioxygenase 1 (IDO1), which generates kynurenine. They hypothesized that an increase in IDO1 and kynurenine, triggered by amyloid and tau protein buildup, disrupts brain metabolism and leads to cognitive decline.

Andreasson explained, “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 harms synapses.”

By blocking the production of kynurenine through IDO1 inhibition, the researchers were able to restore the astrocytes’ ability to nourish neurons with lactate.

One promising aspect of this research is that IDO1 is already well-known in oncology, and drugs to suppress its activity are currently in clinical trials. This allowed the research team to bypass the lengthy process of drug development and quickly test these inhibitors on mice with Alzheimer’s.

The results were promising—mice treated with these drugs showed improved glucose metabolism in the hippocampus, better astrocytic function, and enhanced spatial memory.

Another significant finding was the drug's effectiveness across different Alzheimer’s models. “We also can’t overlook the fact that we saw this improvement in brain plasticity in mice with both amyloid and tau models. These are completely different pathologies, and the drugs appear to work for both,” Andreasson noted. This discovery excited the research team, as it indicates the broad potential of this approach.

The intersection of neuroscience, oncology, and pharmacology could expedite the development of these drugs for Alzheimer’s treatment, should they prove effective in ongoing human clinical trials for cancer. Andreasson remains hopeful, stating, “We’re hopeful that IDO1 inhibitors developed for cancer could be repurposed for treatment of AD.”

The next step for the research team is to test IDO1 inhibitors in human Alzheimer’s patients to determine if the cognitive and memory improvements observed in mice can be replicated in humans.

While previous clinical trials for cancer focused on the drugs' effectiveness against tumors, they did not evaluate their impact on cognition and memory. Andreasson plans to investigate these effects in upcoming trials for Alzheimer’s disease, marking a potential new chapter in the fight against this devastating condition.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

Like these kind of feel good stories? Get The Brighter Side of News' newsletter.