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

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…

• HH
  Howard Hughes Medical Institute

  Award: GT15655
• AD
  Arizona Department of Health Services

  Awards: P30 AG19610, NIA P30 AG19610, U24 NS072026
• JP
  Jean Perkins Foundation
• JA
  Japan Agency for Medical Research and Development
• FP
  Fondation pour la Recherche Médicale
• AB
  Arizona Biomedical Research Commission

  Awards: P30 AG19610, U24 NS072026
• UO
  University of California, San Diego

  Award: P30 AG062429
• WT
  Wu Tsai Neurosciences Institute, Stanford University
• NI
  National Institute on Aging

  Awards: AG062429, U24 NS072026, AG056306, P30 AG062429, P30 AG0066515, AG19610, P30 AG19610
• NI
  National Institute of Neurological Disorders and Stroke

  Awards: U24 NS072026, NS072026, P30 AG19610
• MR
  Moonshot Research and Development Program