Pathogenic Implications of Distinct Patterns of Iron and Zinc in Chronic MS Lesions

Acta Neuropathol. 2017 Jul;134(1):45-64. doi: 10.1007/s00401-017-1696-8. Epub 2017 Mar 22.


Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.

Keywords: Astrocyte; Iron; Multiple sclerosis; Oligodendrocyte; Remyelination; Shadow plaque; Smoldering lesion; Synchrotron; Zinc.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / metabolism
  • Brain Chemistry*
  • Female
  • Ferritins / chemistry
  • Humans
  • Iron / analysis*
  • Macrophages / chemistry
  • Macrophages / pathology
  • Male
  • Microglia / chemistry
  • Microglia / metabolism
  • Middle Aged
  • Multiple Sclerosis / metabolism*
  • Multiple Sclerosis / pathology
  • Remyelination
  • Young Adult
  • Zinc / analysis*


  • Ferritins
  • Iron
  • Zinc