Iron and neurodegeneration in the multiple sclerosis brain
TL;DR: 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.
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TL;DR: It is proposed that the inflammatory demyelinating disease process in early multiple sclerosis triggers a cascade of events that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden.
Abstract: Summary A better understanding of the pathological mechanisms that drive neurodegeneration in individuals with multiple sclerosis is needed to develop therapies that will effectively treat patients in the primary and secondary progressive stages of the disease. We propose that the inflammatory demyelinating disease process in early multiple sclerosis triggers a cascade of events that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden. Key elements driving neurodegeneration include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Altered mitochondrial function in axons might be of particular importance. This process leads to chronic cell stress and imbalance of ionic homoeostasis, resulting in axonal and neuronal death. The evidence suggests that treatment of progressive multiple sclerosis should be based on a combination of anti-inflammatory, regenerative, and neuroprotective strategies.
874 citations
TL;DR: Research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction are reviewed to identify potential novel therapeutic targets in MS.
Abstract: Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the CNS, and imposes major burdens on young lives. Great progress has been made in understanding and moderating the acute inflammatory components of MS, but the pathophysiological mechanisms of the concomitant neurodegeneration--which causes irreversible disability--are still not understood. Chronic inflammatory processes that continuously disturb neuroaxonal homeostasis drive neurodegeneration, so the clinical outcome probably depends on the balance of stressor load (inflammation) and any remaining capacity for neuronal self-protection. Hence, suitable drugs that promote the latter state are sorely needed. With the aim of identifying potential novel therapeutic targets in MS, we review research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction. We focus on mechanisms inherent to neurons and their axons, which are separable from those acting on inflammatory responses and might, therefore, represent bona fide neuroprotective drug targets with the capability to halt MS progression.
503 citations
TL;DR: The plasticity of these signatures of microglia in health and disease is discussed and the mechanisms underlying their establishment, maintenance and regulation are considered.
Abstract: Microglia are the primary innate immune cells in the CNS In the healthy brain, they exhibit a unique molecular homeostatic 'signature', consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment
485 citations
Vita-Salute San Raffaele University1, VU University Amsterdam2, University of Göttingen3, Cleveland Clinic4, John Radcliffe Hospital5, University of Siena6, Mayo Clinic7, University of Nottingham8, Medical University of Graz9, University College London10, Yale University11, University of Saskatchewan12, Medical University of Vienna13
TL;DR: A number of correlative pathological and MRI studies have helped to define in vivo the pathological substrates of MS in focal lesions and normal-appearing white matter, not only in the brain, but also in the spinal cord.
Abstract: Pathological evaluation is the gold standard for identifying processes related to multiple sclerosis that explain disease manifestations, and for guiding the development of new treatments. However, there are limitations to the techniques used, including the small number of donors available, samples often representing uncommon cases, and impossibility of follow-up. Correlative studies have demonstrated that MRI is sensitive to the different pathological substrates of multiple sclerosis (inflammation, demyelination, and neuro-axonal loss). The role of MRI in evaluating other pathological processes, such as leptomeningeal involvement, central vein and rim of lesions, microstructural abnormalities, iron accumulation, and recovery mechanisms, has been investigated. Although techniques used for quantifying pathological processes in different regions of the CNS have advanced diagnosis and monitoring of disease course and treatment of multiple sclerosis, new perspectives and questions have emerged, including how different pathological processes interact over the disease course and when remyelination might occur. Addressing these questions will require longitudinal studies using MRI in large cohorts of patients with different phenotypes.
441 citations
TL;DR: The phenotype of microglia in evolving lesions from patients with multiple sclerosis is analysed and it is found that microglias lose their homeostatic phenotype in active lesions and express activation markers functionally related to tissue injury.
Abstract: Microglia and macrophages accumulate at the sites of active demyelination and neurodegeneration in the multiple sclerosis brain and are thought to play a central role in the disease process We used recently described markers to characterize the origin and functional states of microglia/macrophages in acute, relapsing and progressive multiple sclerosis We found microglia activation in normal white matter of controls and that the degree of activation increased with age This microglia activation was more pronounced in the normal-appearing white matter of patients in comparison to controls and increased with disease duration In contrast to controls, the normal-appearing white matter of patients with multiple sclerosis showed a significant reduction of P2RY12, a marker expressed in homeostatic microglia in rodents, which was completely lost in active and slowly expanding lesions Early stages of demyelination and neurodegeneration in active lesions contained microglia with a pro-inflammatory phenotype, which expressed molecules involved in phagocytosis, oxidative injury, antigen presentation and T cell co-stimulation In later stages, the microglia and macrophages in active lesions changed to a phenotype that was intermediate between pro- and anti-inflammatory activation In inactive lesions, the density of microglia/macrophages was significantly reduced and microglia in part converted to a P2RY12+ phenotype Analysis of TMEM119, which is expressed on microglia but not on recruited macrophages, demonstrated that on average 45% of the macrophage-like cells in active lesions were derived from the resident microglia pool Our study demonstrates the loss of the homeostatic microglial signature in active multiple sclerosis with restoration associated with disease inactivity
427 citations
Cites background or methods from "Iron and neurodegeneration in the m..."
...Thus, the expression of certain microglia/macrophage molecules may also be in part regulated by the iron metabolism, which is disturbed within the multiple sclerosis brain and lesions (Hametner et al., 2013)....
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...Ferritin and ferritin light were found in oligodendrocytes and to a variable extent in microglia or perivascular cells (Hametner et al., 2013)....
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...Digital optical densitometry was performed for markers, which were not exclusively expressed in macrophages and microglia, such as the MHC Class I marker HC10 and ferritin, according to a previously published protocol (Hametner et al., 2013)....
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References
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TL;DR: The description outlined here facilitates the understanding of factors that favour mitochondrial ROS production and develops better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
Abstract: The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The flux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2•− production is far lower. The generation of O2•− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2•− generation by mitochondria in vivo from O2•−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
6,371 citations
"Iron and neurodegeneration in the m..." refers background in this paper
...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 View this article online at wileyonlinelibrary.com....
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...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....
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TL;DR: An overview of redox and non-redox metal-induced formation of free radicals and the role of oxidative stress in toxic action of metals is provided.
2,429 citations
TL;DR: In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI.
Abstract: In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).
1,491 citations
"Iron and neurodegeneration in the m..." refers background in this paper
...This hypothesis is supported by accumulation of oxidized DNA and phospholipids in degenerating oligodendrocytes, axons and neurons in active MS lesions,(28) upregulation of antioxidative defense mechanisms,(40) and effective antioxidative treatment for RRMS patients.(41) Potential sources of oxygen and nitric oxide radicals include oxidative burst(13,42,43) and mitochondrial injury,(12) which has been demonstrated in neurons, demyelinated axons,(14,15) oligodendrocytes, and astrocytes(31) in MS cortex and WM lesions....
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TL;DR: The most extensive and systematic investigations of histologically demonstrable iron in the brain were conducted by SPATZ (1922), which found a fine granular deposit of iron in individual oligodendroglia cells and nerve cells, mainly in the globus pallidus and in the red zone of substantia nigra.
Abstract: IRON is found in the normal brain as haemin iron in haemoglobin and in ironcontaining enzymes and as non-haemin iron. At least part of the non-haemin iron can be shown by histochemical methods, the prussian blue and Turnbull blue reactions being most commonly used to demonstrate it. GUIZZEITI (1915) examined the iron reactions seen when thick, macroscopic brain sections were treated with potassium ferrocyanide or ammonium sulphide. He found that certain parts of the brain gave a stronger staining reaction than others: the globus pallidus, substantia nigra, red nucleus and dentate nucleus were most intensely stained. The most extensive and systematic investigations of histologically demonstrable iron in the brain were conducted by SPATZ (1922). Using thick, macroscopic sections SPATZ was able to divide the centres of the central nervous system into four groups according to their iron content. The first group comprised the globus pallidus and substantia nigra, which gave the most intense and invariable iron reaction. The red nucleus, putamen, caudate nucleus, dentate nucleus and the subthalamic body, with constant but somewhat weaker staining properties, formed the second group. The structures included in the first and second groups belong to the so-called extrapyramidal system. The third group, which included the cerebral and cerebellar cortex, the anterior nucleus of the thalamus, the mamillary body, the tectum of the midbrain and the central grey matter of the third ventricle, gave a variable and considerably weaker reaction for iron. The centres of the fourth group showed no histochemical iron staining; it comprised the medulla oblongata, the grey matter of the spinal cord, the spinal and sympathetic ganglia and the white matter of the brain and the spinal cord. SPATZ also observed that the foetal brain never showed a positive iron reaction. In the first years of life iron could be demonstrated in the extra-pyramidal system and the amount gradually increased until puberty. In microscopical sections from the centres of the two first groups SPATZ observed a diffuse iron reaction visible to the naked eye. He found a fine granular deposit of iron in individual oligodendroglia cells and nerve cells, mainly in the globus pallidus and in the red zone of substantia nigra. These granules could be observed only by using high magnification. HADFIELD (1929) stated that the walls of the blood vessels of the healthy globus pallidus from the age of 30 onward are often infiltrated with iron salts. GELLERSTEDT (1933), when studying the alterations of the brain during normal involution, found granular iron deposits in the motorand occipital cortex of individuals over 65 years of age without nervous or mental disease. These iron deposits were observed only in extremely small amounts in individual oligodendroglia cells,
1,351 citations
"Iron and neurodegeneration in the m..." refers background or result in this paper
...Iron has been shown to increase with age in human brains.(6) Densitometric analysis of the iron content revealed a significant correlation of iron load with age in the 30 controls in the subcortical (see Fig 1A) and deep WM (not shown)....
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...Within the deep white matter (WM), iron content was comparatively low.(6) In line with previous findings,(8,26) most iron in control NWM and MS NAWM was stored in oligodendrocytes and myelin within ferritin (Supplementary Fig 1)....
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TL;DR: It is found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease, and the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.
Abstract: Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.
1,238 citations