Summary: Blocking the kynurenine pathway, a regulator of brain metabolism, can restore cognitive function in lab mice with Alzheimer’s disease. The pathway is overactivated in Alzheimer’s, disrupting glucose metabolism and starving neurons of energy.
By inhibiting this pathway, researchers improved memory and brain plasticity in mice, offering hope for new treatments in humans. IDO1 inhibitors, currently in cancer trials, could be repurposed for Alzheimer’s treatment.
Key Facts:
- Blocking the kynurenine pathway in mice with Alzheimer’s restored brain metabolism and improved memory.
- The kynurenine pathway is overactivated in Alzheimer’s, disrupting glucose metabolism in the brain.
- Drugs targeting this pathway, initially developed for cancer, show promise for Alzheimer’s treatment.
Source: Stanford
Among the many ways neuroscientists think Alzheimer’s disease may strip away brain function is by disrupting the glucose metabolism needed to fuel the healthy brain. In essence, declining metabolism robs the brain of energy, impairing thinking 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.
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, appeared 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.
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.
Promise kept
“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.
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.
About this Alzheimer’s disease and memory research news
Author: Nicholas Weiler
Source: Stanford
Contact: Nicholas Weiler – Stanford
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies” by Katrin Andreasson et al. Science
Abstract
Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies
INTRODUCTION
Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by a progressive and irreversible loss of synapses and neural circuitry. Major pathophysiologic processes that contribute to synaptic loss, including disrupted proteostasis, accumulation of misfolded amyloid and tau, and microglial dysfunction, are being vigorously investigated with the goal of identifying disease-modifying therapies.
However, coincident with these distinct pathologies is a sustained decline in cerebral glucose metabolism, with recent proteomics revealing a marked disruption of astrocytic and microglial metabolism in AD subjects.
RATIONALE
Astrocytes generate lactate that is exported to neurons to fuel mitochondrial respiration and support synaptic activity. Recent studies have suggested a role for indoleamine-2,3-dioxygenase 1 (IDO1), an enzyme expressed in astrocytes, in multiple neurodegenerative disorders, including AD. IDO1 is the rate-limiting enzyme in the conversion of tryptophan (TRP) to kynurenine (KYN), a metabolite that elicits immune suppression in inflammatory and neoplastic contexts through interaction with the aryl-hydrocarbon receptor (AhR).
IDO1 activity is significantly up-regulated by a variety of immunogenic stimuli, and, in the brain, IDO1 is expressed in astrocytes and microglia but not in neurons, where levels can increase in response to inflammatory stimuli.
RESULTS
We report that inhibition of IDO1 and production of KYN rescues hippocampal synaptic plasticity and memory function in preclinical models of amyloid and tau pathology by restoring astrocytic metabolic support of neurons. Activation of IDO1 in astrocytes by amyloid β and tau oligomers, two major pathologic effectors in AD, increases KYN and suppresses glycolysis in an AhR-dependent manner.
Conversely, pharmacological IDO1 inhibition restores astrocytic glycolysis and lactate production. In amyloid-producing APPSwe-PS1∆E9 and 5XFAD mice and in tau-producing P301S mice, IDO1 inhibition improves hippocampal glucose metabolism, as shown by metabolomic and MALDI-MS (matrix-assisted laser desorption ionization–mass spectrometry) analyses, and restores spatial memory.
IDO1 blockade also rescues hippocampal long-term potentiation in a monocarboxylate transporter–dependent manner, suggesting that IDO1 activity disrupts astrocytic metabolic support of neurons. Indeed, in vitro mass labeling of human astrocytes demonstrated that IDO1 regulates astrocyte generation of lactate that is then taken up by human neurons.
In cocultures of astrocytes and neurons derived from AD subjects, deficient astrocyte lactate production and transfer to neurons was corrected by IDO1 inhibition, resulting in improved neuronal glucose metabolism.
CONCLUSION
In addition to uncovering a previously uncharacterized role of IDO1 in brain glucose metabolism, our study highlights the potential of brain penetrant IDO1 inhibitors, developed as an adjunctive therapy for cancer, to be repurposed for treating neurodegenerative diseases such as AD.
This study also reveals a general mechanism contributing to neuronal dysfunction that cuts across distinct pathologies. In addition to AD, manipulation of IDO1 may be relevant to Parkinson’s disease dementia, which is characterized by amyloid accumulation in addition to α-synuclein, as well as the broad spectrum of tauopathies.
There is the possibility that deficient astrocytic glucose metabolism could also underlie other neurodegenerative diseases characterized by the accumulation of other misfolded proteins where increases in kynurenine pathway metabolites have been observed.
