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 language | English |
|---|---|
| Pages (from-to) | 503-517.e8 |
| Journal | Cell metabolism |
| Volume | 31 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 3 2020 |
All Science Journal Classification (ASJC) codes
- Physiology
- Molecular Biology
- Cell Biology
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Impairment of Glycolysis-Derived L-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
In: Cell metabolism, Vol. 31, No. 3, 03.03.2020, p. 503-517.e8.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Impairment of Glycolysis-Derived L-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease
AU - Le Douce, Juliette
AU - Maugard, Marianne
AU - Veran, Julien
AU - Matos, Marco
AU - Jégo, Pierrick
AU - Vigneron, Pierre Antoine
AU - Faivre, Emilie
AU - Toussay, Xavier
AU - Vandenberghe, Michel
AU - Balbastre, Yaël
AU - Piquet, Juliette
AU - Guiot, Elvire
AU - Tran, Nguyet Thuy
AU - Taverna, Myriam
AU - Marinesco, Stéphane
AU - Koyanagi, Ayumi
AU - Furuya, Shigeki
AU - Gaudin-Guérif, Mylène
AU - Goutal, Sébastien
AU - Ghettas, Aurélie
AU - Pruvost, Alain
AU - Bemelmans, Alexis Pierre
AU - Gaillard, Marie Claude
AU - Cambon, Karine
AU - Stimmer, Lev
AU - Sazdovitch, Véronique
AU - Duyckaerts, Charles
AU - Knott, Graham
AU - Hérard, Anne Sophie
AU - Delzescaux, Thierry
AU - Hantraye, Philippe
AU - Brouillet, Emmanuel
AU - Cauli, Bruno
AU - Oliet, Stéphane H.R.
AU - Panatier, Aude
AU - Bonvento, Gilles
N1 - Funding Information: This work was supported by grants from the Centre National de la Recherche Scientifique (G.B., S.H.R.O., and A. Panatier), Agence Nationale de la Recherche ( ANR 2011 MALZ-0003 to G.B. and B.C.), Association France Alzheimer and Fondation de France ( Prix Spécial 2012 to G.B., B.C., and S.H.R.O.), Fondation Plan Alzheimer (G.B.), Infrastructure de Recherche translationnelle pour les Biothérapies en Neurosciences (NeurATRIS ANR-11-INBS-0011 to G.B.), and Fondation pour la Recherche Médicale and EU Joint Programme – Neurodegenerative Disease Research (JPND; Horizon 2020 Framework Programme, grant agreement 643417/DACAPO-AD to S.H.R.O.). J.L.D. is a recipient of a PhD fellowship from the CEA (IRTELIS program). M. Maugard is a recipient of a PhD fellowship from the Ecole Normale Supérieure (ENS). P.-A.V. is a recipient of a PhD fellowship from the Fondation pour la Recherche Médicale (FRM). P.J.’s fellowship was provided by Enhanced Eurotalents, a Marie Sklodowska-Curie Actions Programme, co-funded by the European Commission and managed by the Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA). M. Matos is a recipient of a post-doctoral fellowship (DACAPO-AD/JPND/EU H20H20 grant agreement N°643417). This work benefited from the support of various facilities granted by INSERM and LabEX BRAIN ANR-10-LABX-43. The team of G.B. is part of the Ecole des Neurosciences de Paris (ENP) training network and that of S.H.R.O is part of the LabEx BRAIN. Funding Information: The authors thank Martine Guillermier and Sueva Bernier for useful technical help; and Felipe Barros, Juan Bolanos, and Igor Allaman for helpful discussion. We thank No?lle Dufour and Charl?ne Jos?phine for viral production, the Neuro-CEB biobank at the H?pital de la Piti?-Salp?tri?re for providing human samples, Anaelle Dubois for electron microscopy at the BioEM Facility of the EPFL (Switzerland), and Alain Ch?dotal and St?phane Fouquet at the Institut de la Vision for high resolution scans. We also thank Delphine Gonzales, Sara Laumond, and everyone at the animal and genotyping facilities of the NeuroCentre Magendie for mouse care and genotyping. This work was supported by grants from the Centre National de la Recherche Scientifique (G.B. S.H.R.O. and A. Panatier), Agence Nationale de la Recherche (ANR 2011 MALZ-0003 to G.B. and B.C.), Association France Alzheimer and Fondation de France (Prix Sp?cial 2012 to G.B. B.C. and S.H.R.O.), Fondation Plan Alzheimer (G.B.), Infrastructure de Recherche translationnelle pour les Bioth?rapies en Neurosciences (NeurATRIS ANR-11-INBS-0011 to G.B.), and Fondation pour la Recherche M?dicale and EU Joint Programme ? Neurodegenerative Disease Research (JPND; Horizon 2020 Framework Programme, grant agreement 643417/DACAPO-AD to S.H.R.O.). J.L.D. is a recipient of a PhD fellowship from the CEA (IRTELIS program). M. Maugard is a recipient of a PhD fellowship from the Ecole Normale Sup?rieure (ENS). P.-A.V. is a recipient of a PhD fellowship from the Fondation pour la Recherche M?dicale (FRM). P.J.?s fellowship was provided by Enhanced Eurotalents, a Marie Sklodowska-Curie Actions Programme, co-funded by the European Commission and managed by the Commissariat ? l'Energie Atomique et aux Energies Alternatives (CEA). M. Matos is a recipient of a post-doctoral fellowship (DACAPO-AD/JPND/EU H20H20 grant agreement N?643417). This work benefited from the support of various facilities granted by INSERM and LabEX BRAIN ANR-10-LABX-43. The team of G.B. is part of the Ecole des Neurosciences de Paris (ENP) training network and that of S.H.R.O is part of the LabEx BRAIN. J.L.D. performed the confocal analysis, carried out the biochemical, qRT-PCR and the metabolic studies and developed the AAVs with the help of M. Maugard, A.-P.B. and M.-C.G.; J.V. and M. Matos performed electrophysiology on 3xTg-AD mice with the help of A. Panatier; M. Maugard performed all experiments on Phgdhflox/flox mice, immunoblotting, and all behavioral tests with the help of K.C.; P.J. carried out electrophysiology on Phgdhflox/flox mice; P.-A.V. P.J. and M.G.-G. performed microdialysis; N.T.T. M.T. S.G. A.G. and A. Pruvost measured extracellular amino acid concentrations using CE-LIF or LC-MS/MS; E.F. performed the histological analysis of the 3xTg-AD colony and performed the in vivo metabolic study with the help of G.B. and M.G.-G.; X.T. carried out the FRET imaging experiments with the help of J.P. E.G. and B.C.; M.V. Y.B. A.-S.H. and T.D. performed the 3D image processing and analysis of the in vivo metabolic data; S.M. and M. Maugard measured extracellular D-serine using biosensors; A.K. and S.F. provided the Phgdhflox/flox mice and measured amino acid concentrations using HPLC; L.S. V.S. and C.D. performed and analyzed immunohistochemical staining on human samples with the help of P.-A.V.; G.K. performed EM studies; P.H. and E.B. provided materials and discussed the data; B.C. S.H.R.O. and G.B. obtained funding for the research; and A. Panatier and G.B. coordinated the study and wrote the manuscript. The authors declare no competing interests. Publisher Copyright: © 2020 Elsevier Inc.
PY - 2020/3/3
Y1 - 2020/3/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85080076503&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85080076503&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2020.02.004
DO - 10.1016/j.cmet.2020.02.004
M3 - Article
C2 - 32130882
AN - SCOPUS:85080076503
SN - 1550-4131
VL - 31
SP - 503-517.e8
JO - Cell Metabolism
JF - Cell Metabolism
IS - 3
ER -