1. Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease
Juliette Le Douce, et al. Cell Metab. 2020 Mar 3;31(3):503-517.e8. 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.
2. l-Serine links metabolism with neurotransmission
Marianne Maugard, Pierre-Antoine Vigneron, Juan P Bolaños, Gilles Bonvento Prog Neurobiol. 2021 Feb;197:101896. doi: 10.1016/j.pneurobio.2020.101896. Epub 2020 Aug 14.
Brain energy metabolism is often considered as a succession of biochemical steps that metabolize the fuel (glucose and oxygen) for the unique purpose of providing sufficient ATP to maintain the huge information processing power of the brain. However, a significant fraction (10-15 %) of glucose is shunted away from the ATP-producing pathway (oxidative phosphorylation) and may be used to support other functions. Recent studies have pointed to the marked compartmentation of energy metabolic pathways between neurons and glial cells. Here, we focused our attention on the biosynthesis of l-serine, a non-essential amino acid that is formed exclusively in glial cells (mostly astrocytes) by re-routing the metabolic fate of the glycolytic intermediate, 3-phosphoglycerate (3PG). This metabolic pathway is called the phosphorylated pathway and transforms 3PG into l-serine via three enzymatic reactions. We first compiled the available data on the mechanisms that regulate the flux through this metabolic pathway. We then reviewed the current evidence that is beginning to unravel the roles of l-serine both in the healthy and diseased brain, leading to the notion that this specific metabolic pathway connects glial metabolism with synaptic activity and plasticity. We finally suggest that restoring astrocyte-mediated l-serine homeostasis may provide new therapeutic strategies for brain disorders.
3. Glycolysis-derived L-serine levels versus PHGDH expression in Alzheimer's disease
Gilles Bonvento, Stéphane H R Oliet, Aude Panatier Cell Metab. 2022 May 3;34(5):654-655. doi: 10.1016/j.cmet.2022.04.002.
Recent work from Bonvento and colleagues indicated that synaptic and memory deficits in early Alzheimer's disease (AD) are related to a shortage in L-serine production in astrocytes. Here, the authors, responding to correspondence from Chen and colleagues, discuss how this deficiency does not necessarily require a decrease in PHGDH expression and conclude that the primary event leading to lower serine production is more likely related to altered glycolytic flux in early AD than to PHGDH expression.
