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

Cell Metabolism
Juliette Le DouceGilles Bonvento

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.

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Citations

Jul 2, 2020·International Journal of Molecular Sciences·Elena RosiniLoredano Pollegioni
Jul 1, 2020·Cellular and Molecular Life Sciences : CMLS·Giulia MurtasLoredano Pollegioni
Nov 17, 2020·Frontiers in Cellular Neuroscience·Susanne KöhlerUlrike Winkler
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May 18, 2021·Frontiers in Neuroscience·Xin ZhangLiqin Zhao
Jun 3, 2021·International Journal of Molecular Sciences·Sarah L NolinCecilia Giulivi
Jun 3, 2021·International Journal of Molecular Sciences·Chia-Yuan ChangWen-Sung Lai
Jun 13, 2021·Progress in Neurobiology·Shuai ZhangXiaofeng Jia
Jul 25, 2021·International Journal of Molecular Sciences·Mark W SherwoodAude Panatier

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