Iron in multiple sclerosis: roles in neurodegeneration and repair

Abstract

MRI and histological studies have shown global alterations in iron levels in the brains of patients with multiple sclerosis (MS), including increases in the iron stored by macrophages and microglia. Excessive free iron can be toxic, and accumulation of iron in MS has generally been thought to be detrimental. However, iron maintains the integrity of oligodendrocytes and myelin, and facilitates their regeneration following injury. The extracellular matrix, a key regulator of remyelination, might also modulate iron levels. This Review highlights key histological and MRI studies that have investigated changes in iron distribution associated with MS. Potential sources of iron, as well as iron regulatory proteins and the detrimental roles of excessive iron within the CNS, are also discussed, with emphasis on the importance of iron within cells for oxidative metabolism, proliferation and differentiation of oligodendrocytes, and myelination. In light of the beneficial and detrimental properties of iron within the CNS, we present considerations for treatments that target iron in MS. Such treatments must balance trophic and toxic properties of iron, by providing sufficient iron levels for remyelination and repair while avoiding excesses that might overwhelm homeostatic mechanisms and contribute to damage.