TY - JOUR
T1 - Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies
AU - Minhas, Paras S.
AU - Jones, Jeffrey R.
AU - Latif-Hernandez, Amira
AU - Sugiura, Yuki
AU - Durairaj, Aarooran S.
AU - Wang, Qian
AU - Mhatre, Siddhita D.
AU - Uenaka, Takeshi
AU - Crapser, Joshua
AU - Conley, Travis
AU - Ennerfelt, Hannah
AU - Jung, Yoo Jin
AU - Liu, Ling
AU - Prasad, Praveena
AU - Jenkins, Brenita C.
AU - Ay, Yeonglong Albert
AU - Matrongolo, Matthew
AU - Goodman, Ryan
AU - Newmeyer, Traci
AU - Heard, Kelly
AU - Kang, Austin
AU - Wilson, Edward N.
AU - Yang, Tao
AU - Ullian, Erik M.
AU - Serrano, Geidy E.
AU - Beach, Thomas G.
AU - Wernig, Marius
AU - Rabinowitz, Joshua D.
AU - Suematsu, Makoto
AU - Longo, Frank M.
AU - McReynolds, Melanie R.
AU - Gage, Fred H.
AU - Andreasson, Katrin I.
PY - 2024/8/23
Y1 - 2024/8/23
N2 - 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.
AB - 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.
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U2 - 10.1126/science.abm6131
DO - 10.1126/science.abm6131
M3 - Article
C2 - 39172838
AN - SCOPUS:85202001853
SN - 0036-8075
VL - 385
SP - eabm6131
JO - Science (New York, N.Y.)
JF - Science (New York, N.Y.)
IS - 6711
ER -
