Summary: Blocking the kynurenine road, a regulation of mental stamina, you restore mental work in laboratory animals with Alzheimer’s disease. Alzheimer’s overactivates the insulin metabolism road, starving neurons of power, and causing this to happen.
Experts improved memory and brain flexibility in mice by inhibiting this road, giving rise to new treatments for humans. IDO1 antagonists, now in cancer tests, may be repurposed for Alzheimer’s care.
Important Information:
- In animals with Alzheimer’s, blocking the kynurenine pathway restored head metabolism and storage.
- Alzheimer’s suffers from a kynurenine overactivation, which causes a disruption in glucose metabolism in the mind.
- Drugs targeting this road, originally developed for cancers, show promises for Alzheimer’s treatment.
Origin: Stanford
Neuroscientists believe that Alzheimer’s disease may impair mental function by preventing the glucose metabolism required to maintain healthy brain function. In fact, declining digestion robs the brain of power, impairing thinking and memory.
A group of researchers from Stanford’s Wu Tsai Neurosciences Institute have focused on the kynurenine road, a crucial regulation of mental stamina.
They make the claim that the kynurenine pathway  is overactivated as a result of the amyloid plaque and beta enzymes that accumulate in the brains of Alzheimer’s disease sufferers.
Then, 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 may increase, or even recover, mental work by reinstating healthy brain stamina.
” We were surprised that these physiological enhancements were so successful at not only preserving good connections, but in actually , rescuing , conduct. When we gave the animals drugs that blocked the kynurenine pathway, they performed better on cognitive and memory tests, according to older writer,  , Katrin Andreasson, a physician at the Stanford School of Medicine and a part 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 theory was that brain function would be hampered and cognitive decline would result from increases in IDO1 and kynurenine due to the accumulation of amyloid and tau proteins.
” Astomatic cells, a crucial cell type that metabolically supports neurons, have an overactivated kynurenine pathway.  , 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.
A blockade of IDO1’s kinase production restores astrocytes ‘ ability to provide lactate to neurons.
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 enabled Andreasson to skip the labor-intensive work of finding new drugs and to begin testing in lab mice almost right away.
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 ca n’t ignore the fact that we observed this improvement in brain plasticity in mice using both amyloid and tau mice models. These are completely different pathologies, and the drugs appear to work for both”, Andreasson noted. That really excited us, they said.
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 optimistic that cancer-derived IDO1 inhibitors can be used again to treat AD, Andreasson said.
The next step is to test IDO1 inhibitors on human Alzheimer’s patients to see if they produce comparable improvements in memory and cognition. Prior clinical trials in cancer patients evaluated the potency of IDO1 inhibitors on cancer but did not anticipate or assess changes 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&,# 39, s disease pathologies” by Katrin Andreasson et al. Science
Abstract
Restoring hippocampal glucose metabolism rescues cognition across Alzheimer&,# 39, s disease pathologies
INTRODUCTION
Alzheimer’s disease ( AD ) is an age-related neurodegenerative disorder that causes a progressive and irreversible loss of neural circuitry and synapses. 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, in addition to these distinct pathologies, there is a persistent decline in cerebral glucose metabolism, recent proteomics showing a marked decline in astrocytic and microglial metabolism in AD subjects.
RATIONALE
Lactate is produced by astrocytes and 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. The rate-limiting enzyme in the conversion of tryptophan ( TRP ) to kynurenine ( KYN), a metabolite that interacts with the aryl-hydrocarbon receptor ( AhR ) in inflammatory and neoplastic settings, is IDO1.
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
In preclinical models of amyloid and tau pathology, we report that inhibition of IDO1 and KYN-induced reversal of hippocampal synaptic plasticity and memory function by restoring astrocytic metabolic support of neurons. The two main pathologic effectors of AD, amyloid and tau oligomers, increase KYN and inhibit glycolysis in an AhR-dependent manner, by activating IDO1 in astrocytes.
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. In fact, in vitro mass labeling of human astrocytes demonstrated that IDO1 regulates the production of lactate by astrocytes, which is then absorbed by human neurons.
IDO1 inhibition helped to improve neuronal glucose metabolism in cocultures of astrocytes and neurons from AD subjects.
CONCLUSION
Our study highlights the potential of brain-penetrant IDO1 inhibitors, developed as an adjunctive therapy for cancer, being repurposed for treating neurodegenerative diseases like AD in addition to revealing a previously undiscovered role of IDO1 in brain glucose metabolism.
This study also reveals a broad mechanism that accounts for neuronal dysfunction and covers a range of 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.
Other neurodegenerative diseases characterized by the accumulation of other misfolded proteins where increases in kynurenine pathway metabolites have been observed may also be related to deficient astrocytic glucose metabolism.
