Format

Send to

Choose Destination
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.

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: aude.panatier@inserm.fr.
13
Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France. Electronic address: gilles.bonvento@cea.fr.

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.

KEYWORDS:

3xTg-AD mice; NMDA; PHGDH; d-serine; glia; glucose; hippocampus; spatial memory; synaptic plasticity

PMID:
32130882
DOI:
10.1016/j.cmet.2020.02.004

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center