A study that was published in Science on August 22 was able to demonstrate that by modifying a crucial metabolic pathway in the brain—the kynurenine pathway—scientists were able to improve, and in some cases restore, cognitive functioning in Alzheimer’s cases in mice by reinstating healthy brain metabolism. The study was conducted by neuroscientists at the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute, in collaboration with researchers at the Salk Institute for Biological Studies, Penn State University, and others.
The kynurenine pathway (KP), first discovered in 1853, when functioning normally is crucial for generating cellular energy and catabolizing tryptophan. Tryptophan is an essential amino acid, and is important for the availability of niacin to the body; a deficiency in niacin can lead to conditions such as pellagra. When tryptophan is metabolized by serotonin (a key hormone), it affects mood, sleep and perception of pain.
Dysregulation of the KP can affect a wide array of bodily functions—neurological disorders (depression, schizophrenia), auto-immune diseases (MS, HIV, and RA), the cardiovascular system, the gastrointestinal tract, and neurodegenerative illnesses, such as Alzheimer’s and Parkinson’s diseases. The KP also regulates production of lactate, which nourishes the brain’s neurons and helps maintain healthy synapses (most people are familiar with it in the form of lactic acid, after strenuous exercise).
SciTechDaily reported that in this instance, the 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.” It also noted that “IDO1 is well known in oncology and there are already drugs in clinical trials to suppress IDO1 activity and production of kynurenine. That meant [the researchers] could circumvent the time-intensive work of identifying new drugs and to begin testing in lab mice almost immediately.”
“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,” said senior author, Katrin Andreasson, a neurologist at the Stanford School of Medicine and member of the Wu Tsai Neurosciences Institute. “Blocking production of kynurenine by blocking IDO1 restores the ability of astrocytes to nourish neurons with lactate…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.”
SciTechDaily noted that 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.”
For further reading: “What Is the Tryptophan Kynurenine Pathway and Why Is It Important to Neurotherapy?” NIH National Library of Medicine.
