Characterization of myelin lipid changes across disease stages in experimental autoimmune encephalomyelitis 2302268

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The myelin sheath of the CNS is a highly specialized, lipid-rich membrane that acts as the primary target of autoimmunity in MS, leading to demyelination, axonal injury, and consequent neuronal dysfunction. While the immunopathogenesis of MS has been extensively studied, particularly autoreactive lymphocytes, cytokine networks, and myelin sheath targeted immune responses, the contribution of lipid metabolism to disease progression mechanisms remains relatively underexplored. Here, we investigated whether neuroinflammation promoted alterations in the myelin lipidome during the initial attack of disease and during disease relapses that could contribute to MS progression. We used mass spectrometry imaging (MSI), thiobarbituric acid reactant (TBARS) assays, and integrated immunohistochemistry to characterize lipid profiles, peroxidation, and spatial distribution in relapsing-remitting experimental autoimmune encephalomyelitis (EAE) models across disease stages. We identified significant lipid peroxidation during the acute phase of disease, with levels remaining elevated throughout remission, spatial heterogeneity of myelin sheath sulfatide distribution in the central nervous system, and disease-specific lipid modifications corresponding to inflammatory infiltrates, supporting the pathogenic role of oxidized lipids in MS. These findings provide novel insights into the dynamics of the CNS lipidome during neuroinflammation and suggest that myelin lipid alterations could contribute to MS progression through mechanisms independent of neuroinflammation. R21 NS137101-01 Neuroimmunology (NEUR)