Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease.
Administration, Oral
Aged
Aged, 80 and over
Alzheimer Disease
/ drug therapy
Animals
Astrocytes
/ drug effects
Binding Sites
Brain
/ pathology
Cognitive Dysfunction
/ metabolism
Energy Metabolism
/ drug effects
Female
Glucose
/ metabolism
Glycolysis
/ drug effects
Humans
Male
Mice, Transgenic
Middle Aged
Neuronal Plasticity
/ drug effects
Phosphoglycerate Dehydrogenase
/ metabolism
Receptors, N-Methyl-D-Aspartate
/ metabolism
Serine
/ administration & dosage
Spatial Memory
/ drug effects
3xTg-AD mice
NMDA
PHGDH
d-serine
glia
glucose
hippocampus
spatial memory
synaptic plasticity
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
03 03 2020
03 03 2020
Historique:
received:
25
07
2019
revised:
25
10
2019
accepted:
07
02
2020
entrez:
5
3
2020
pubmed:
5
3
2020
medline:
2
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32130882
pii: S1550-4131(20)30063-2
doi: 10.1016/j.cmet.2020.02.004
pii:
doi:
Substances chimiques
Receptors, N-Methyl-D-Aspartate
0
Serine
452VLY9402
Phosphoglycerate Dehydrogenase
EC 1.1.1.95
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
503-517.e8Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.