2020
DOI: 10.1016/j.cmet.2020.02.004
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Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer’s Disease

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,… Show more

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Cited by 167 publications
(108 citation statements)
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“…Astrocytic L-serine was proposed to regulate NMDAR activity to sustain D-serine production by neurons [91] that J o u r n a l P r e -p r o o f would thus explain the altered synaptic plasticity observed in AD. The deficits of functional plasticity in the hippocampus and memory impairments in these 3xTg-AD mice [84] are rescued by long-term treatments with either D-or L-serine, confirming the view of severe metabolic dysfunction as a leading hallmark and cause of AD as previously proposed (see [92]).…”
Section: D-serine In Alzheimer's Diseasesupporting
confidence: 83%
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“…Astrocytic L-serine was proposed to regulate NMDAR activity to sustain D-serine production by neurons [91] that J o u r n a l P r e -p r o o f would thus explain the altered synaptic plasticity observed in AD. The deficits of functional plasticity in the hippocampus and memory impairments in these 3xTg-AD mice [84] are rescued by long-term treatments with either D-or L-serine, confirming the view of severe metabolic dysfunction as a leading hallmark and cause of AD as previously proposed (see [92]).…”
Section: D-serine In Alzheimer's Diseasesupporting
confidence: 83%
“…Indeed, observations from two transgenic mice models have extended the debate into the preclinical field on how D-serine contributes to AD. In fact, a decreased synthesis of L-serine from glucose though PHGDH astrocytic enzyme has recently been reported in 3xTg-AD mice [84]. Astrocytic L-serine was proposed to regulate NMDAR activity to sustain D-serine production by neurons [91] that J o u r n a l P r e -p r o o f would thus explain the altered synaptic plasticity observed in AD.…”
Section: D-serine In Alzheimer's Diseasementioning
confidence: 97%
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“…The metabolism of the brain is realized by a joint effort of all cell types including neurons, glial cells as well as cells constituting the blood vessels. Almost all aspects of metabolism in the brain involve several types of cells, including energy metabolism (Pellerin and Magistretti, 1994;Guzmán and Blázquez, 2001; Barros and Deitmer, 2010;Nave, 2010a;Hirrlinger and Nave, 2014;Barros et al, 2018b;Díaz-García and Yellen, 2019;Vicente-Gutierrez et al, 2019;Zuend et al, 2020), and neurotransmitter metabolism (van den Berg et al, 1978;Waagepetersen et al, 2003;Bak et al, 2006;Le Douce et al, 2020). Furthermore, brain cells are structurally intermingled, heavily interdigitating their numerous cellular processes (Somjen, 1988;Grosche et al, 1999;Bushong et al, 2002;Nave, 2010b).…”
Section: Introductionmentioning
confidence: 99%
“…We found that glucose, glycolytic and TCA cycle substrates, and glutathione are among the top accumulated metabolites. Suppressed glycolysis and dysfunctional TCA cycle that may lead to increased glucose and other intermediate metabolites, and elevated glutathione in response to reactive oxygen species, have been reported in AD (Atamna and Frey II 2007; Mandal et al 2019; Le Douce et al 2020). On the other hand, molecules involve in DNA synthesis and valine/leucine/isoleucine metabolism are most depleted in the AD neuron cells, which are consistent to the recently reported observations of suppressed DNA synthesis and valine metabolism in AD (Yurov et al 2011; Polis and Samson 2020).…”
Section: Resultsmentioning
confidence: 98%