Young Scientific Investigators’ Session 1Wednesday, October 02, 2013, 14:24 - 14:36
Iron and oxidative damage in the multiple sclerosis brainS. Hametner, I. Wimmer, L. Haider, S. Pfeifenbring, W. Brück, H. Lassmann (Vienna, AT; Göttingen, DE)
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to oligodendrocyte destruction, demyelination and neurodegeneration. Iron in the healthy human CNS is essentially stored within oligodendrocytes and myelin. However, excess or liberated iron has the ability to induce oxidative damage and is therefore implicated in various neurodegenerative disorders. We aimed to characterize the impact of iron liberation from degenerating oligodendrocytes and myelin on tissue damage in MS. Formalin-fixed, paraffin-embedded autopsy brain tissue of 33 MS cases, including 7 acute MS cases, and 30 controls were studied. With a subset of 4 acute MS and 3 control cases, whole-genome microarrays were performed in order to analyze mRNA expression levels of iron-related genes. For detection of non-heme iron, the diaminobenzidine-enhanced Turnbull blue staining was applied. The iron storage protein ferritin, the microglia markers Iba-1 and CD68, the ferroxidases hephaestin and ceruloplasmin, and oxidized phospholipids as markers for oxidative stress (E06 epitope) were detected by immunohistochemistry. Microarray analysis revealed up-regulation of cytoplasmic ferritin, mitochondrial ferritin, ferroxidases as well as downregulation of the mitochondrial iron exporter frataxin in acute MS lesions, suggesting iron-related cellular and mitochondrial stress. Compared to controls, MS brains showed a global reduction of iron in non-lesioned white matter oligodendrocytes and myelin, which was significantly correlated with MS disease duration. In active lesions, we observed a shift of iron storage and ferritin expression from oligodendrocytes to microglia/macrophages. Iron-loaded microglia displayed dystrophic morphology and were significantly reduced towards inactive lesion centers, where iron was either completely removed or stored within astrocytes and axons. A minor proportion of late active lesions harboured elevated amounts of iron in astrocytes and axons. E06-positive axonal spheroids were most abundant in early active lesions, where extracellular iron could be detected. Rarely, a direct colocalization of iron and oxidized phospholipids was observed.
Conclusions: MS leads to a global iron loss in the brain white matter. Demyelination in MS leads to waves of iron liberation from intracellular stores, which may promote oxidative damage.
All listed authors have nothing to disclose.