SPATIAL METABOLOMICS REVEALS REGION-SPECIFIC METABOLIC ALTERATIONS IN PROGRESSIVE MULTIPLE SCLEROSIS

Progressive multiple sclerosis (P-MS) is a major challenge for neuroscience due to the lack of effective therapies and the complexity of its pathogenesis. P-MS is characterized by chronic neuroinflammation, demyelination, neurodegeneration, and metabolic alterations in both immune and neuronal cells. However, the relationship between metabolic impairment and disease progression remains poorly understood. To address this gap in knowledge, we employed the chronic experimental autoimmune encephalomyelitis (cEAE) mouse model at the chronic stage (30-60 days after disease induction), which recapitulates some key features of P-MS, to investigate disease-related metabolic changes. Spatial mass spectrometry (SMS) was applied to perform spatial metabolomics in spinal cord sections from wild-type (WT) and cEAE mice (n = 5 for condition). This analysis enabled high-resolution metabolic mapping and discrimination between gray matter, white matter, and perispinal tissue. Moreover, cEAE mice exhibited pronounced region specific metabolic alterations. Pathway enrichment analysis revealed dysregulation of phospholipid metabolism in gray matter, while white matter showed broader alterations in amino acid metabolism, lipid metabolism, and the tricarboxylic acid cycle. Spatial autocorrelation analysis using Moran’s Index demonstrated increased metabolite clustering in cEAE tissue, reflecting localized metabolic remodeling. Metabolites involved in inflammatory and excitotoxic pathways, including arachidonic acid and amino acid-related metabolites, displayed strong spatial clustering in diseased tissue, consistent with focal inflammation and degeneration. In conclusion, our findings indicate that progressive neuroinflammation is associated with distinct and spatially organized metabolic changes, highlighting SMS as a powerful tool to uncover region-specific metabolic mechanisms underlying P-MS progression.