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

Science. 2024 Aug 23;385(6711):eabm6131. doi: 10.1126/science.abm6131. Epub 2024 Aug 23.

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.

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides* / metabolism
  • Animals
  • Astrocytes* / metabolism
  • Cognition / drug effects
  • Disease Models, Animal
  • Glucose* / metabolism
  • Glycolysis* / drug effects
  • Hippocampus* / metabolism
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase* / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase* / metabolism
  • Kynurenine* / metabolism
  • Lactic Acid / metabolism
  • Long-Term Potentiation
  • Male
  • Memory / drug effects
  • Mice
  • Monocarboxylic Acid Transporters / metabolism
  • Neurons* / metabolism
  • Receptors, Aryl Hydrocarbon / metabolism
  • Tryptophan / metabolism
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Glucose
  • IDO1 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Kynurenine
  • Lactic Acid
  • Monocarboxylic Acid Transporters
  • Receptors, Aryl Hydrocarbon
  • tau Proteins
  • Tryptophan