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 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.
Authors
- Brenita C. Jenkins
- Hannah Ennerfelt (ORCID: https://orcid.org/0000-0003-4861-0740)
- Traci Fang Newmeyer
- Melanie R. McReynolds (ORCID: https://orcid.org/0000-0001-5427-2739)
- Jeffrey R. Jones (ORCID: https://orcid.org/0000-0002-7570-2571)
- Praveena Prasad (ORCID: https://orcid.org/0009-0002-1485-4798)
- Frank M. Longo (ORCID: https://orcid.org/0000-0002-9514-7325)
- Yoo Jin Jung (ORCID: https://orcid.org/0000-0002-9015-5529)
- Aarooran S. Durairaj (ORCID: https://orcid.org/0000-0001-9355-3111)
- Katrin I. Andreasson (ORCID: https://orcid.org/0000-0001-8391-4155)
- Ling Liu (ORCID: https://orcid.org/0000-0001-6413-708X)
- Makoto Suematsu (ORCID: https://orcid.org/0000-0002-7165-6336)
- Edward Norman Wilson (ORCID: https://orcid.org/0000-0003-0640-5247)
- Paras S. Minhas (ORCID: https://orcid.org/0000-0002-7741-3327)
- Matthew Matrongolo
- Geidy E. Serrano (ORCID: https://orcid.org/0000-0002-9527-2011)
- Joshua D. Rabinowitz (ORCID: https://orcid.org/0000-0002-1247-4727)
- Erik M. Ullian (ORCID: https://orcid.org/0000-0003-2077-8584)
- Kelly J. Heard (ORCID: https://orcid.org/0000-0001-7719-7225)
- Travis E. Conley
- Amira Latif‐Hernandez
- Yuki Sugiura (ORCID: https://orcid.org/0000-0002-6983-8958)
- Thomas G. Beach (ORCID: https://orcid.org/0000-0003-3296-6128)
- Fred H. Gage (ORCID: https://orcid.org/0000-0002-0938-4106)
- Takeshi Uenaka (ORCID: https://orcid.org/0000-0001-5786-5038)
- Joshua Crapser (ORCID: https://orcid.org/0000-0002-8426-2336)
- Marius Wernig (ORCID: https://orcid.org/0000-0002-5309-515X)
- Siddhita D. Mhatre (ORCID: https://orcid.org/0000-0001-9939-780X)
- Ryan Goodman (ORCID: https://orcid.org/0009-0007-4828-2675)
- Austin Kang (ORCID: https://orcid.org/0009-0007-0288-3029)
- Qian Wang (ORCID: https://orcid.org/0009-0003-6246-883X)
- Yeonglong Albert Ay (ORCID: https://orcid.org/0009-0000-2255-3042)
- Tao Yang (ORCID: https://orcid.org/0000-0002-7698-3440)
Institutions
- Salk Institute for Biological Studies (US)
- Pennsylvania State University (US)
- Meiji University (JP)
- University of California, San Francisco (US)
- Neurosciences Institute (US)
- Princeton University (US)
- Central Institute for Experimental Animals (JP)
- Kyoto University (JP)
- Chan Zuckerberg Initiative (United States) (US)
- Banner Sun Health Research Institute (US)
- Stanford University (US)
Publication Details
- Journal
- Science
- Published
- 2024-08-22
- DOI
- https://doi.org/10.1126/science.abm6131
- Citations
- 165
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 25.81
Funders
- Howard Hughes Medical Institute
- Arizona Department of Health Services
- Jean Perkins Foundation
- Japan Agency for Medical Research and Development
- Fondation pour la Recherche Médicale
- Arizona Biomedical Research Commission
- University of California, San Diego
- Wu Tsai Neurosciences Institute, Stanford University
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke
- Moonshot Research and Development Program