Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer’s Disease

• Published in: Cell metabolism Vol. 31; no. 3; pp. 503 - 517.e8
• Main Authors: Le Douce, Juliette, Maugard, Marianne, Veran, Julien, Matos, Marco, Jégo, Pierrick, Vigneron, Pierre-Antoine, Faivre, Emilie, Toussay, Xavier, Vandenberghe, Michel, Balbastre, Yaël, Piquet, Juliette, Guiot, Elvire, Tran, Nguyet Thuy, Taverna, Myriam, Marinesco, Stéphane, Koyanagi, Ayumi, Furuya, Shigeki, Gaudin-Guérif, Mylène, Goutal, Sébastien, Ghettas, Aurélie, Pruvost, Alain, Bemelmans, Alexis-Pierre, Gaillard, Marie-Claude, Cambon, Karine, Stimmer, Lev, Sazdovitch, Véronique, Duyckaerts, Charles, Knott, Graham, Hérard, Anne-Sophie, Delzescaux, Thierry, Hantraye, Philippe, Brouillet, Emmanuel, Cauli, Bruno, Oliet, Stéphane H.R., Panatier, Aude, Bonvento, Gilles
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2020; Elsevier
• Subjects: 3xTg-AD mice; d-serine; glia; glucose; hippocampus; Life Sciences; Neurobiology; Neurons and Cognition; NMDA; PHGDH; spatial memory; synaptic plasticity; glucose; hippocampus; 3xTg-AD mice; d-serine; spatial memory; NMDA; PHGDH; synaptic plasticity; glia; spatial behavior; Astrocytes; L-serine; Alzheimer's Disease
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2020.02.004

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. [Display omitted] •Astrocytes have impaired glycolytic flux in a mouse model of Alzheimer’s disease•Consequently, astrocytes produce less glycolysis-derived l-serine•Low NMDAR occupancy by d-serine leads to impairment of synaptic plasticity and memory•Dietary supplementation of l-serine restores synaptic plasticity and memory Le Douce et al. show that glycolysis is impaired in astrocytes in the early stages of disease in a mouse model of Alzheimer’s. This leads to the reduction of both l- and d-serine synthesis and to the alteration of synaptic plasticity and memory. Dietary supplementation with l-serine restores both deficits, suggesting it to be a potential therapy.