KAUST Research Workshop on Innovative Technologies to Study Brain Energy Metabolism
CEA - François Jacob Institute of Biology, France
Professor Bonvento is Research Director at the CEA - François Jacob Institute of Biology. His currently research focus is on the interactions between neurons and astrocytes, at the fundamental level but also in the context of neurodegenerative diseases in which glial cells display an activated. Field of expertise: Neuron-glia interactions – energy metabolism – in vivo rodent models of neurodegenerative diseases.
Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département de la Recherche Fondamentale, Institut François Jacob, Molecular Imaging Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, Fontenay-aux-Roses, France
A decrease of brain glucose metabolism occurs early in specific brain regions of Alzheimer's disease (AD) patients. These metabolic alterations correlate with disease progression and even predict histopathological diagnosis. However, it is still unclear whether, and how, glucose dysregulation contributes to synaptic defects and memory impairment in AD. Recent observations suggest that changes in aerobic glycolysis prevail in the early phase of AD. Aside from ATP production, a major function of glycolysis is to provide precursors, such as L-serine, to support macromolecular synthesis. L-serine is the precursor of D-serine, the principal co-agonist of synaptic N-methyl D-aspartate receptors (NMDARs) required for the induction of long-term synaptic plasticity in the hippocampus. Yet, the potential contribution of glycolysis-derived L-serine to early synaptic plasticity and behavioral deficits in AD is unknown. Here we show that phosphoglycerate dehydrogenase (Phgdh), the first enzyme of the L-serine pathway, is mainly expressed in astrocytes in mouse and human brain. Silencing Phgdh in mouse hippocampal astrocytes impairs both long-term synaptic plasticity and spatial memory. Expression of Phgdh is significantly reduced in patients who are positive for both amyloid-β and Tau pathology. AD mice, at early stage of the disease, exhibit alterations of glucose metabolism that translates into a reduced glycolytic flux in astrocytes, decreased L-serine levels and a reduced occupancy of the NMDAR co-agonist site. Accordingly, acute application of D-serine or L-serine rescues long-term synaptic plasticity and chronic oral L-serine supplementation restores memory deficits in AD mice. Altogether these results indicate that a metabolic deficit of L-serine synthesis by astrocytes contributes to cognitive deficits in AD. Our findings highlight L-serine as a potential therapeutic target for AD as well as other neurodegenerative diseases and reveal that astrocytic energy metabolism controls cognitive functions.