Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer’s Disease
Cell Metabolism. 2020-03-01; 31(3): 503-517.e8
DOI: 10.1016/j.cmet.2020.02.004
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1. Cell Metab. 2020 Mar 3;31(3):503-517.e8. doi: 10.1016/j.cmet.2020.02.004.
Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to
Cognitive Deficits in Alzheimer’s Disease.
Le Douce J(1), Maugard M(1), Veran J(2), Matos M(2), Jégo P(1), Vigneron PA(1),
Faivre E(1), Toussay X(3), Vandenberghe M(1), Balbastre Y(1), Piquet J(3), Guiot
E(3), Tran NT(4), Taverna M(5), Marinesco S(6), Koyanagi A(7), Furuya S(7),
Gaudin-Guérif M(1), Goutal S(1), Ghettas A(8), Pruvost A(8), Bemelmans AP(1),
Gaillard MC(1), Cambon K(1), Stimmer L(9), Sazdovitch V(10), Duyckaerts C(10),
Knott G(11), Hérard AS(1), Delzescaux T(1), Hantraye P(1), Brouillet E(1), Cauli
B(3), Oliet SHR(2), Panatier A(12), Bonvento G(13).
Author information:
(1)Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies
Neurodégénératives, Fontenay-aux-Roses, France.
(2)Neurocentre Magendie, INSERM U1215, Bordeaux, France; Université de Bordeaux,
Bordeaux, France.
(3)Sorbonne Université, CNRS, INSERM, Neurosciences Paris Seine – Institut de
Biologie Paris Seine (NPS-IBPS), Paris, France.
(4)Université Paris-Saclay, CNRS, Institut Galien Paris Sud, Châtenay-Malabry,
France.
(5)Université Paris-Saclay, CNRS, Institut Galien Paris Sud, Châtenay-Malabry,
France; Institut Universitaire de France (IUF), Paris, France.
(6)AniRA-NeuroChem Technological Platform, Lyon Neuroscience Research Center,
CNRS, UMR 5292, INSERM U1028, University Claude Bernard Lyon 1, Lyon, France.
(7)Laboratory of Functional Genomics and Metabolism, Department of Bioscience and
Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences,
Kyushu University, Fukuoka, Japan.
(8)Université Paris-Saclay, CEA, INRAE, Département Médicaments et technologies
pour la santé, Gif-sur-Yvette, France.
(9)INSERM US27, Platform for Experimental Pathology, MIRCen, Fontenay-aux-Roses,
France.
(10)Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la
Pitié-Salpêtrière, AP-HP, Paris, France.
(11)BioEM Facility, School of Life Sciences, Swiss Federal Institute of
Technology Lausanne (EPFL), Lausanne, Switzerland.
(12)Neurocentre Magendie, INSERM U1215, Bordeaux, France; Université de Bordeaux,
Bordeaux, France. Electronic address: .
(13)Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies
Neurodégénératives, Fontenay-aux-Roses, France. Electronic address:
.
Comment in
Cell Metab. 2020 Mar 3;31(3):439-440.
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.
Copyright © 2020 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cmet.2020.02.004
PMID: 32130882
Conflict of interest statement: Declaration of Interests The authors declare no
competing interests.