Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration

Abstract

Neurodegenerative disorders are characterized by the presence of inflammation in areas with neuronal cell death and a regional increase in iron that exceeds what occurs during normal aging. The inflammatory process accompanying the neuronal degeneration involves glial cells of the central nervous system (CNS) and monocytes of the circulation that migrate into the CNS while transforming into phagocytic macrophages. This review outlines the possible mechanisms responsible for deposition of iron in neurodegenerative disorders with a main emphasis on how iron-containing monocytes may migrate into the CNS, transform into macrophages, and die out subsequently to their phagocytosis of damaged and dying neuronal cells. The dying macrophages may in turn release their iron, which enters the pool of labile iron to catalytically promote formation of free-radical-mediated stress and oxidative damage to adjacent cells, including neurons. Healthy neurons may also chronically acquire iron from the extracellular space as another principle mechanism for oxidative stress-mediated damage. Pharmacological handling of monocyte migration into the CNS combined with chelators that neutralize the effects of extracellular iron occurring due to the release from dying macrophages as well as intraneuronal chelation may denote good possibilities for reducing the deleterious consequences of iron deposition in the CNS.

Iron chelation in the treatment of neurodegenerative diseases

“…Macrophages may be attracted to phagocyte iron accumulated due to damage of ironrich oligodendrocytes and neurons. Alternatively, iron-containing activated phagocytic cells that migrate into the CNS as part of the inflammatory response may be themselves the source of abnormal iron deposits [10]. This view has been supported by a study employing a rat model of substantia nigra degeneration induced by ibotenic acid where the neurodegeneration was accompanied by an influx of iron-laden macrophages [11].…”

New findings about iron oxide nanoparticles and their different effects on murine primary brain cells

“…32,33 Iron deposits in activated microglia have also been found to be a notable feature in neurodegenerative diseases, including multiple sclerosis and Alzheimer's and Parkinson's disease, leading to homeostatic imbalance and even cell death. 32,34,35 The use of SPIOs as contrast agents in MRI is especially critical, because whether or not particles interact with brain …”

“…Free iron ions and the formation of intracellular iron deposits most likely contribute to increasing levels of microglial cell death by impairing mitochondrial function. 32,34,35 Therefore, the facilitated accumulation of highly concentrated VSOPs or ferucarbotran by microglia is most likely the cause for the consistent decrease of microglial viability over 24 hours, which is caused by intracellular particle localization as well as individual SPIO composition, including size, coating, surface charge, and concentration.…”

“…42,50,73 Therefore, ferumoxytol was able to degrade rapidly after it was added to cell cultures, resulting in the release of free iron ions and extracellular iron deposits, which might subsequently adversely affect microglial physiology in the long term. 34,35 Accordingly, we assume that those elevated iron levels could strongly impair the endocytotic activity of microglia due to altered enzyme function. The exposure to ferumoxytol in high doses might diminish microglial particle accumulation over an extended period of time.…”

Quantitative Susceptibility Mapping of the Thalamus: Relationships with Thalamic Volume, Total Gray Matter Volume, and T2 Lesion Burden

“…21 Alternatively, iron may accumulate as a result of inflammation along tracts that connect with the thalamus, with activated microglia along these tracts expressing high levels of ferritin [22][23][24][25] and iron being released by degenerating oligodendrocytes and myelin fibers. As iron imaging becomes more recognized as a marker of disease in multiple sclerosis, 26 it will become increasingly important to understand the pathophysiologic basis for changes in iron relative to existing markers of atrophy and lesion burden.…”