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Le métabolisme astrocytaire de la L-sérine et ses implications dans la maladie d'Alzheimer : une potentielle approche thérapeutique

Pierre-Antoine Vigneron 1
1 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
MIRCEN - Service MIRCEN : DRF/JACOB, CNRS - Centre National de la Recherche Scientifique : UMR 9199
Abstract : Subtle losses of memory or changes in behavior are the first outward signs of Alzheimer’s disease (AD). AD patients often display concomitant reduced glucose metabolism as observed by 18F- fluorodeoxyglucose PET. Whether such energy metabolism deficit contributes to cognitive impairment in AD is still not known. In the brain, oxidative use of glucose provides most of the ATP required to fuel synaptic activity. However, recent observations suggest that changes in aerobic glycolysis prevail in the early phase of AD. The phosphorylated pathway diverts 3-phosphoglycerate from the glycolytic flux, to produce de novo L-serine through the action of three enzymes (PHDGH, PSAT1 and PSPH). Astrocytes are the main source of L-serine in the brain. We made the hypothesis that a dysfunction in astrocyte L-serine production, resulting from an altered ener-gy metabolism, could participate in the deficits observed in AD. We used 3xTg-AD mice, a mouse model that recapitulates metabolic and synaptic deficits in addition to classical AD hallmarks. We measured the level of L-serine in the hippocampus of these mice and found it was decreased compared to controls. Consequently, we supplemented them with a 10%-L-serine-enriched diet during 2 months which rescued their synaptic and cognitive deficits. To unveil the mechanisms underlying such beneficial effects of L-serine we focused on its participation in lipid synthesis. We analyzed cell morphology using 3D-reconstruction and found neuron morphology was not altered but the territory covered by astrocytes is decreased and can be fully restored by L-serine diet. To further identify the impact of this diminution on neurotransmission we assessed the astrocytic coverage of hippocampal synapses, using electron microscopy. Together, these results suggest a critical role for astrocyte L-serine in synaptic plasticity and memory.
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Pierre-Antoine Vigneron. Le métabolisme astrocytaire de la L-sérine et ses implications dans la maladie d'Alzheimer : une potentielle approche thérapeutique. Neurobiologie. Université Paris-Saclay, 2020. Français. ⟨NNT : 2020UPASL016⟩. ⟨tel-02976106⟩

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