Journal
CELL METABOLISM
Volume 31, Issue 3, Pages 503-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2020.02.004
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Funding
- Centre National de la Recherche Scientifique
- Agence Nationale de la Recherche [ANR 2011 MALZ-0003]
- Association France Alzheimer
- Fondation de France
- Fondation Plan Alzheimer
- Infrastructure de Recherche translationnelle pour les Biotherapies en Neurosciences [NeurATRIS ANR-11INBS-0011]
- Fondation pour la Recherche Medicale
- EU Joint Programme - Neurodegenerative Disease Research (JPND
- Horizon 2020 Framework Programme) [643417/DACAPO-AD]
- CEA (IRTELIS program)
- Ecole Normale Superieure (ENS)
- Fondation pour la Recherche Medicale (FRM)
- Enhanced Eurotalents, a Marie Sklodowska-Curie Actions Programme
- European Commission
- DACAPO-AD/JPND/EU H20H20 grant agreement [643417]
- INSERM
- LabEX BRAIN [ANR-10-LABX-43]
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Alteration of brain aerobic glycolysis is often observed early in the course of Alzheimer's disease (AD). Whether and how such metabolic dysregulation contributes to both synaptic plasticity and behavioral deficits in AD is not known. Here, we show that the astrocytic L-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients. L-serine is the precursor of D-serine, a co-agonist of synaptic NMDA receptors (NMDARs) required for synaptic plasticity. Accordingly, AD mice display a lower occupancy of the NMDAR co-agonist site as well as synaptic and behavioral deficits. Similar deficits are observed following inactivation of the L-serine synthetic pathway in hippocampal astrocytes, supporting the key role of astrocytic L-serine. Supplementation with L-serine in the diet prevents both synaptic and behavioral deficits in AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral L-serine as a ready-to-use therapy for AD.
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