Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies

• Published in: Science Vol. 385; no. 6711; p. eabm6131
• Main Authors: Minhas, Paras S., Jones, Jeffrey R., Latif-Hernandez, Amira, Sugiura, Yuki, Durairaj, Aarooran S., Wang, Qian, Mhatre, Siddhita D., Uenaka, Takeshi, Crapser, Joshua, Conley, Travis, Ennerfelt, Hannah, Jung, Yoo Jin, Liu, Ling, Prasad, Praveena, Jenkins, Brenita C., Ay, Yeonglong Albert, Matrongolo, Matthew, Goodman, Ryan, Newmeyer, Traci, Heard, Kelly, Kang, Austin, Wilson, Edward N., Yang, Tao, Ullian, Erik M., Serrano, Geidy E., Beach, Thomas G., Wernig, Marius, Rabinowitz, Joshua D., Suematsu, Makoto, Longo, Frank M., McReynolds, Melanie R., Gage, Fred H., Andreasson, Katrin I.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 23.08.2024; The American Association for the Advancement of Science
• Subjects: Accumulation; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; Astrocytes; Astrocytes - metabolism; Brain; Cell activation; Cell culture; Circuits; Cognition; Cognition - drug effects; Dementia disorders; Disease; Disease Models, Animal; Enzymes; Fuels; Glucose; Glucose - metabolism; Glycolysis; Glycolysis - drug effects; Hippocampus; Hippocampus - metabolism; Humans; Immunogenicity; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Inflammation; Inhibition; Ionization; Kynurenine - metabolism; Lactic acid; Lactic Acid - metabolism; Long-Term Potentiation; Male; Mass spectrometry; Mass spectroscopy; Memory; Memory - drug effects; Memory tasks; Metabolism; Metabolites; Mice; Microglia; Monocarboxylic Acid Transporters - metabolism; Neural networks; Neurodegenerative diseases; Neurogenesis; Neurons; Neurons - metabolism; Oligomers; Parkinson's disease; Pathology; Plasticity; Pluripotency; Protein folding; Proteins; Proteomics; Receptors, Aryl Hydrocarbon - metabolism; Spatial analysis; Stem cells; Stimuli; Synapses; Synaptic plasticity; tau Proteins - metabolism; Tryptophan; Tryptophan - metabolism
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abm6131

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. 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