2024-08-22 ペンシルベニア州立大学(PennState)
<関連情報>
- https://www.psu.edu/news/research/story/cancer-drug-could-treat-early-stage-alzheimers-disease-study-shows/
- https://www.science.org/doi/10.1126/science.abm6131
海馬のグルコース代謝を回復させると、アルツハイマー病の病態を超えて認知機能が回復する Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies
Paras S. Minhas, Jeffrey R. Jones, Amira Latif-Hernandez, Yuki Sugiura https://orcid.org/0000-0002-6983-8958, […], and Katrin I. Andreasson
Science Published:23 Aug 2024
DOI:https://doi.org/10.1126/science.abm6131
Editor’s summary
Alzheimer’s disease has been associated with brain metabolic alterations. Minhas et al. studied the role of glucose metabolism impairments on disease progression using a combination of human induced pluripotent stem cells and mouse models (see the Perspective by Johnson and Macauley). The authors showed that activation of indoleamine-2,3-dioxygenase 1 (IDO1) by either amyloid β or tau oligomers, two prominent Alzheimer’s disease pathological proteins, promotes the conversion of tryptophan to kynurenine, which then suppresses astrocytic glycolysis, thus reducing one of the main fuel sources for neurons. Inhibiting IDO1 rescued synaptic plasticity in vitro and improved cognition in multiple rodent models. Targeting metabolic dysfunctions holds promise for the treatment of neurodegenerative disorders. —Mattia Maroso
Structured Abstract
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.
Mechanism of action of astrocytic IDO1 activity across AD pathologies.
(Left) Astrocytes (in green) generate lactate, and glycolytic gene expression is partly regulated by hypoxia-inducible factor 1-α (HIF1α). Sufficient lactate is transferred from the astrocyte to the neuron (in blue) to fuel neuronal mitochondrial respiration and synaptic activity. (Middle) Astrocytic IDO1 generation of KYN increases, disrupting the balance between AhR and HIF1α nuclear signaling and reducing astrocytic glycolysis, lactate production, and metabolic support of neuronal activity. (Right) Decreased astrocyte KYN restores glycolysis and metabolic support of neurons and reduces the severity of amyloid and tau pathologies. [Figure created with BioRender.com]
Abstract
Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer’s disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid β and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor–dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter–dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.
