Iron and neurodegeneration in the multiple sclerosis brain
Open accessAbstract
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 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. METHODS: We performed (1) whole-genome microarrays including 4 MS and 3 control cases to analyze the expression of iron-related genes, (2) nonheme 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) corresponding with disease duration, when corrected for age. This decrease of iron in oligodendrocytes and myelin was associated with an upregulation 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.
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Conditions such as MS, Cuprizone-fed and Shiverer mice are often used in validation studies because of known effect on myelin, but they also affect iron metabolism and axons.
“Conditions such as MS, or animal models such as Cuprizone-fed and Shiverer mice, are often used in validation studies, because of their known effect on myelin, but they also affect iron metabolism, due to iron’s role in myelin maintenance (e.g. Hametner, Wimmer, Haider, Pfeifenbring, Brück, Lassmann, 2013, Pandur, Pap, Varga, Jánosa, Komoly, Fórizs, Sipos, 2019, Sergeant, Vesvres, Devès, Guillou,”
From Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology (2021) · cites this paper as Hametner et al., 2013
The Discussion reports altered iron metabolism in MS lesions and normal-appearing white matter, including iron loss from myelin. The Results also describe iron accumulation in axons at MS lesion edges. The paper does not establish that cuprizone-fed or Shiverer mice have these effects or that these conditions are often used in validation studies. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIron deprivation showed some beneficial improvements in MS patients.
“Indeed, iron deprivation reduced EAE, a T cell dependent autoimmune mouse model of MS (Grant et al., 2003) and importantly, showed some beneficial improvements in MS patients (Hametner et al., 2013; Weigel et al., 2014).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Hametner et al., 2013
During progressive stages of multiple sclerosis, microglia accumulate iron.
“During the progressive stages of MS, microglia have been shown to accumulate iron151,152.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [151]
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- Authors
- Hametner, S., Wimmer, I., Haider, L., Pfeifenbring, S., Brück, W., & Lassmann, H.
- Affiliations
- Medical University of Vienna (AT)
- Universitätsmedizin Göttingen (DE)
- Corresponding author
- Lassmann, Hans
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2013-10-07
- Volume
- 74
- Issue
- 6
- Pages
- 848-861
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4223935
- OpenAlex
- W1742765381
- Cited by
- 519
- References
- 54
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 46 · 2023: 43 · 2022: 61 · 2021: 38 · 2020: 29 · 2019: 42 · 2018: 47 · 2017: 38 · 2016: 47 · 2015: 28 · 2014: 29 · 2013: 5 · 2012: 1
- FWCI
- 27.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- Austrian Science Fund (Project P24245-B19)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- multiple sclerosis, iron accumulation, neurodegeneration, non-heme iron, ferritin, hephaestin, ceruloplasmin, ferroxidase, oligodendrocytes, myelin, normal-appearing white matter, disease duration, microglia, macrophages, astrocytes, oxidative damage, iron metabolism
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Brain, Cell Count, Ceruloplasmin, Child, Female, Ferritins, Humans, Iron, Male, Middle Aged, Multiple Sclerosis, Neurodegenerative Diseases, Iron-Binding Proteins, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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