Iron and neurodegeneration in the multiple sclerosis brain(01/08/13)

This study looked at the distribution of non-heme iron as well as the expression of the iron-related proteins ferritin, hephaestin and ceruloplasmin as regards the oxidative damage in the brain tissue of 33 people with MS and 30 controls. 

The researchers found an age related increase of iron in the white matter of controls and in people with MS with a short disease duration. They found a significant decrease of iron in normal appearing white matter (NAWM) in people with chronic MS. 

The decrease of iron in oligodendrocytes and myelin was associated with an up-regulation of iron-exporting ferroxidases. In active lesions, iron was released from dying oligodenrdocytes with a resulting accumulation of extracelluar iron and uptake into microglia and macrophages. These iron containing macrophages showed signs of cell degeneration. At the edge of lesions the researchers found that iron accumulated in astrocytes and axons. Overall, these results show a decrease in iron in NAWM of people with MS with increasing disease duration. The researchers propose that cellular degeneration in MS lesions leads to waves of iron release, which may be involved in the progression of neurodegeneration in addition to the inflammatory oxidative burst.

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 non-heme 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 in order to analyze the expression of iron-related genes, (2) non-heme 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) with disease duration, when corrected for age. This decrease of iron in oligodendrocytes and myelin was associated with an up-regulation 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. 

Interpretation: 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. 

Hametner S, Wimmer I, Haider L, Pfeifenbring S, Brück W, Lassmann H.

Department for Neuroimmunology, Center for Brain Research, Medical University of Vienna, Austria.

Source: ANN NEUROL 2013. © 2013 American Neurological Association & Pubmed PMID: 23868451 (01/08/13)