title: Iron and neurodegeneration in the multiple sclerosis brain.
abstract: OBJECTIVE
  Iron may contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain with age. Our study focused on nonheme iron distribution and the expression of the iron-related proteins ferritin, hephaestin, and ceruloplasmin in relation to oxidative damage in the brain tissue of 33 MS and 30 control cases.
  
  
  METHODS
  We performed (1) whole-genome microarrays including 4 MS and 3 control cases to analyze the expression of iron-related genes, (2) nonheme iron histochemistry, (3) immunohistochemistry for proteins of iron metabolism, and (4) quantitative analysis by digital densitometry and cell counting in regions representing different stages of lesion maturation.
  
  
  RESULTS
  We found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration. In chronic MS, however, there was a significant decrease of iron in the normal-appearing white matter (NAWM) corresponding with disease duration, when corrected for age. This decrease of iron in oligodendrocytes and myelin was associated with an upregulation of iron-exporting ferroxidases. In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages. Iron-containing microglia showed signs of cell degeneration. At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons.
  
  
  CONCLUSIONS
  Iron decreases in the NAWM of MS patients with increasing disease duration. Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst.
authors.affiliation: Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Hametner
authors.forename: Isabella
authors.initials: I
authors.lastname: Wimmer
authors.forename: Lukas
authors.initials: L
authors.lastname: Haider
authors.forename: Sabine
authors.initials: S
authors.lastname: Pfeifenbring
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count / Q000379:methods; D002570:Ceruloplasmin / Q000378:metabolism; D002648:Child; D005260:Female; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D033862:Iron-Binding Proteins; D005293:Ferritins; D007501:Iron; D002570:Ceruloplasmin