| Literature DB >> 32130882 |
Juliette Le Douce1, Marianne Maugard1, Julien Veran2, Marco Matos2, Pierrick Jégo1, Pierre-Antoine Vigneron1, Emilie Faivre1, Xavier Toussay3, Michel Vandenberghe1, Yaël Balbastre1, Juliette Piquet3, Elvire Guiot3, Nguyet Thuy Tran4, Myriam Taverna5, Stéphane Marinesco6, Ayumi Koyanagi7, Shigeki Furuya7, Mylène Gaudin-Guérif1, Sébastien Goutal1, Aurélie Ghettas8, Alain Pruvost8, Alexis-Pierre Bemelmans1, Marie-Claude Gaillard1, Karine Cambon1, Lev Stimmer9, Véronique Sazdovitch10, Charles Duyckaerts10, Graham Knott11, Anne-Sophie Hérard1, Thierry Delzescaux1, Philippe Hantraye1, Emmanuel Brouillet1, Bruno Cauli3, Stéphane H R Oliet2, Aude Panatier12, Gilles Bonvento13.
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.Entities:
Keywords: 3xTg-AD mice; NMDA; PHGDH; d-serine; glia; glucose; hippocampus; spatial memory; synaptic plasticity
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Year: 2020 PMID： 32130882 DOI： 10.1016/j.cmet.2020.02.004
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287