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Title: Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulatesmore » concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Furthermore, upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.« less

Authors:
 [1];  [2];  [3];  [1];  [1];  [1];  [4];  [4];  [5];  [1];  [1];  [1];  [5];  [6];  [6];  [4];  [4];  [4]
  1. Univ. of Saskatchewan, Saskatoon (Canada)
  2. Medical Univ. Vienna, Vienna (Austria)
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States)
  4. Mayo Clinic, Rochester, MN (United States)
  5. Univ. of Gottingen, Gottingen (Germany)
  6. Medical Univ. of Vienna, Vienna (Austria)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), High Energy Physics (HEP) (SC-25)
OSTI Identifier:
1372893
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Acta Neuropathologica
Additional Journal Information:
Journal Volume: 134; Journal Issue: 1; Journal ID: ISSN 0001-6322
Publisher:
Springer
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; synchrotron; iron; zinc; multiple sclerosis; oligodendrocyte; smoldering lesion; shadow plaque; astrocyte; remyelination

Citation Formats

Popescu, Bogdan F., Frischer, Josa M., Webb, Samuel M., Tham, Mylyne, Adiele, Reginald C., Robinson, Christopher A., Fitz-Gibbon, Patrick D., Weigand, Stephen D., Metz, Imke, Nehzati, Susan, George, Graham N., Pickering, Ingrid J., Bruck, Wolfgang, Hametner, Simon, Lassmann, Hans, Parisi, Joseph E., Yong, Guo, and Lucchinetti, Claudia F.. Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions. United States: N. p., 2017. Web. doi:10.1007/s00401-017-1696-8.
Popescu, Bogdan F., Frischer, Josa M., Webb, Samuel M., Tham, Mylyne, Adiele, Reginald C., Robinson, Christopher A., Fitz-Gibbon, Patrick D., Weigand, Stephen D., Metz, Imke, Nehzati, Susan, George, Graham N., Pickering, Ingrid J., Bruck, Wolfgang, Hametner, Simon, Lassmann, Hans, Parisi, Joseph E., Yong, Guo, & Lucchinetti, Claudia F.. Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions. United States. doi:10.1007/s00401-017-1696-8.
Popescu, Bogdan F., Frischer, Josa M., Webb, Samuel M., Tham, Mylyne, Adiele, Reginald C., Robinson, Christopher A., Fitz-Gibbon, Patrick D., Weigand, Stephen D., Metz, Imke, Nehzati, Susan, George, Graham N., Pickering, Ingrid J., Bruck, Wolfgang, Hametner, Simon, Lassmann, Hans, Parisi, Joseph E., Yong, Guo, and Lucchinetti, Claudia F.. Wed . "Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions". United States. doi:10.1007/s00401-017-1696-8. https://www.osti.gov/servlets/purl/1372893.
@article{osti_1372893,
title = {Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions},
author = {Popescu, Bogdan F. and Frischer, Josa M. and Webb, Samuel M. and Tham, Mylyne and Adiele, Reginald C. and Robinson, Christopher A. and Fitz-Gibbon, Patrick D. and Weigand, Stephen D. and Metz, Imke and Nehzati, Susan and George, Graham N. and Pickering, Ingrid J. and Bruck, Wolfgang and Hametner, Simon and Lassmann, Hans and Parisi, Joseph E. and Yong, Guo and Lucchinetti, Claudia F.},
abstractNote = {Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Furthermore, upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.},
doi = {10.1007/s00401-017-1696-8},
journal = {Acta Neuropathologica},
number = 1,
volume = 134,
place = {United States},
year = {Wed Mar 22 00:00:00 EDT 2017},
month = {Wed Mar 22 00:00:00 EDT 2017}
}

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