Elisa Maffioli (Milan / IT), Valentina Rabattoni (Varese / IT), Farida Tripodi (Milan / IT), Simona Nonnis (Milan / IT), Zoraide Motta (Varese / IT), Silvia Sacchi (Varese / IT), Anna Maria Rinaldi (Rome / IT), Paola Coccetti (Milan / IT), Loredano Pollegioni (Varese / IT), Gabriella Tedeschi (Milan / IT)
During aging, the brain experiences metabolic shifts, particularly involving glucose metabolism and insulin signaling. In Alzheimer's disease (AD), there is a known correlation between cerebral hypometabolism and synaptic activity decline. Astrocytes play a pivotal role in this context, as the glycolytic pathway in these cells supports the production of L-serine (L-Ser), necessary for the synthesis of biomolecules crucial for neuronal function, such as glycine (Gly) and D-serine (D-Ser), which act as co-agonists of N-methyl-D-aspartate (NMDA) receptors. In the brain, de novo L-Ser synthesis proceeds via the phosphorylated pathway (PP), involving three key enzymes: 3-phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP) (1).
Multi-omics investigations comparing hippocampal samples from healthy individuals (CTR) and AD patients revealed metabolic alterations, prominently affecting serine metabolism and disclosing for the first time a gender difference. Increased levels of PHGDH and PSAT in AD were associated with a significant decrease of L-Ser levels and an increase of D-/(D+L)-serine ratio (2). This aligns with prior research linking serine dysfunction to various neurological and psychiatric disorders. Since AD pathology also involves astrocyte impairment, the results prompted us to investigate into astrocyte differentiation and D-Ser's role in astrocyte-central nervous system communication. Multi-omics analysis of NSC-derived human astrocytes underline metabolic changes during astrocytes differentiation and reveal restricted D-Ser synthesis in differentiated astrocytes (3). Moreover, the overexpression of the three enzymes of the PP in hiPSC-derived astrocytes leads to significant alterations not only in serine metabolism pathways but also in folate and nucleotide metabolism and TCA cycle, suggesting a complex metabolic rewiring. This study is aimed to develop new approaches to address brain diseases related to alterations of D-Ser concentration.
This work was supported by PRIN 2017 2017H4J3AS-Dissecting serine metabolism in the brain.
(1) Murtas et al. (2020) Cell Mol Life Sci. 77(24):5131-5148
(2) Maffioli et al. (2022) Cell Rep. 40(10): 111271
(3) Tripodi et al. (2023) FEBS J. 290(18):4440-4464.