Impairment of Glycolysis-Derived L-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease

Juliette Le Douce, Marianne Maugard, Julien Veran, Marco Matos, Pierrick Jégo, Pierre Antoine Vigneron, Emilie Faivre, Xavier Toussay, Michel Vandenberghe, Yaël Balbastre, Juliette Piquet, Elvire Guiot, Nguyet Thuy Tran, Myriam Taverna, Stéphane Marinesco, Ayumi Koyanagi, Shigeki Furuya, Mylène Gaudin-Guérif, Sébastien Goutal, Aurélie GhettasAlain Pruvost, Alexis Pierre Bemelmans, Marie Claude Gaillard, Karine Cambon, Lev Stimmer, Véronique Sazdovitch, Charles Duyckaerts, Graham Knott, Anne Sophie Hérard, Thierry Delzescaux, Philippe Hantraye, Emmanuel Brouillet, Bruno Cauli, Stéphane H.R. Oliet, Aude Panatier, Gilles Bonvento

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)503-517.e8
JournalCell metabolism
Volume31
Issue number3
DOIs
Publication statusPublished - Mar 3 2020

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Le Douce, J., Maugard, M., Veran, J., Matos, M., Jégo, P., Vigneron, P. A., ... Bonvento, G. (2020). Impairment of Glycolysis-Derived L-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease. Cell metabolism, 31(3), 503-517.e8. https://doi.org/10.1016/j.cmet.2020.02.004