Iron and neurodegeneration in the multiple sclerosis brain

TLDR: This 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.

Abstract: Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) leading to oligodendrocyte destruction, demyelination, remyelination, astrocytic scar formation, and neurodegeneration, all being associated with inflammation.1 Effective immunomodulatory therapies target inflammation and subsequent clinical relapses in patients with relapsing–remitting MS (RRMS).2 In contrast, current therapeutic options in primary progressive MS (PPMS) or secondary progressive MS (SPMS) largely remain limited to symptomatic relief. Several factors might prevent therapeutic efficacy,3 among which abnormal iron deposition has recently gained particular interest.4,5 Iron accumulates with increasing age in the healthy human brain, being most prominent after the age of 40 to 50 years,6 which is the time window for patients starting with either PPMS or SPMS.7 Most iron found in the human brain parenchyma is stored as nonheme iron in oligodendrocytes and myelin.8 Iron within the catalytic center of various enzymes is essential for normal brain metabolism, for example, oxidative phosphorylation and myelination.9 In liberated form, however, ferrous iron ions may generate toxic reactive oxygen species (ROS).10 ROS lead to harmful oxidation of lipids and DNA within their immediate vicinity, which is termed oxidative damage. Moreover, mitochondria are both vulnerable to and, if injured, a source of elevated ROS.11,12 Mitochondrial injury is related to oxidative damage in MS.13–15 Oligodendrocytes, which are besides myelin the primary target of inflammatory attacks in MS, are especially vulnerable to such injury.16 Several pathological studies have focused on iron in MS.17–19 We present a study of 63 well-characterized MS and control autopsy cases, examining nonheme iron load as well as the expression of proteins involved in iron metabolism. Our current data on the altered distribution of iron in the brains of MS patients suggest that its liberation within active lesions may amplify demyelination and neurodegeneration.