Cancer drug may help treat early-stage symptoms

For the study, researchers from Stanford University, Kyoto University, Princeton University, the Salk Institute and Penn State examined the effect of an enzyme present in astrocytes on neuronal signaling in the hippocampus, a part of the brain responsible for memory and learning.

Neurons in the brain are supplied with lactate, the production of which is regulated by the molecule kynurenine.

IDO1 is an enzyme that plays a role in the conversion of the amino acid tryptophan (TRY) to kynurenine (KYN). KYN is known to play a role in brain aging and neurodegenerative diseases.

This conversion produces downstream metabolites that play a role in immune regulation. The team had already studied this metabolic pathway before, but this time they focused on the enzyme IDO1.

The team had originally been studying the immune mechanisms underlying brain injury when they decided to explore an inflammatory pathway associated with prostaglandin E2.

When they studied the metabolism of TRY to KYN, they found that the enzyme IDO1, which regulates this pathway, behaved differently than expected in a mouse model of Alzheimer's, said study author Katrin Andreasson, MD, professor of neurology and neurological sciences at Stanford University. Medical news today.

“We tested the role of IDO1 in a model of amyloid accumulation in mice and found the exact opposite of what we expected. This naturally piqued our interest, so we dug deeper and found that this pathway is very important in a completely different type of cell, astrocytes. But not so much in immune cells. So we then focused on astrocytes and their metabolic support of neurons.”

— Katrin Andreasson, MD, study co-author

Researchers were able to detect IDO1 activity in astrocytes but not in neurons of mice, suggesting that the signaling pathway they were studying only occurs in these cells.

They hypothesized that the enzyme IDO1 was increased in astrocytes in the presence of amyloid-beta and tau, two proteins present in people with Alzheimer's disease.

They found that genes responsible for the expression of IDO1 increased significantly in mouse astrocytes exposed to amyloid beta and tau proteins. They also discovered that a subsequent increase in KYN led to a decrease in glucose metabolism in astrocytes.

The results confirmed the researchers' hypothesis that disruption of the homeostasis of this metabolic pathway could play a role in the impaired glucose metabolism observed in Alzheimer's patients.

Further experiments on mouse neurons in the laboratory showed that the use of a cancer immunotherapy that blocks IDO1 activity, PF068, resulted in a dose-dependent increase in glycolysis and mitochondrial respiration in astrocytes but not in neurons.

The researchers then administered the cancer drug to Alzheimer's mice for a month and tested the mice's memory using the maze test.

The results showed that the drug was able to improve the memory of mice. Further analysis of their hippocampal tissues showed that the increase in KYN observed in mouse models of Alzheimer's with accumulation of amyloid-beta was blocked by PF068. This suggests that the rescue of these mice's memory after administration of the drug was due to the interruption of this signaling pathway.

Further experiments were conducted on human brain tissue, including from people with Alzheimer's disease, and showed an increase in KYN, but not TRP, in patients who died with more severe dementia symptoms.

The researchers also generated astrocytes derived from human induced pluripotent stem cells (iPSCs) from patients with late-onset Alzheimer's disease, which showed that the deficit in glucose metabolism was normalized after IDO1 inhibition with PF068.

Andreasson said the team hopes to study patient-derived astrocytes in younger and older patients, as well as in patients with other neurological diseases, in the future to explore this mechanism in those groups.

David Merrill, MD, PhD, a board-certified geriatric psychiatrist at Providence Saint John's Health Center in Santa Monica, California, and holder of the Singleton Endowed Chair in Integrative Brain Health, said: MNT He would be happy to see clinical trials on metabolic interventions for Alzheimer's disease.

“Altered glucose metabolism is associated with Parkinson's, Huntington's and multiple sclerosis. We hypothesize that alterations in glucose metabolism may contribute to the neurodegenerative changes that occur in other neurological diseases,” said Merrill.

“We might see benefits from using metformin, ketogenic diets or GLP-1 agonists. This is an exciting area of ​​active clinical research.”