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

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.

doi:10.1007/s00401-017-1696-8

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

Journal Article · Wed Mar 22 00:00:00 EDT 2017 · Acta Neuropathologica

DOI:https://doi.org/10.1007/s00401-017-1696-8· OSTI ID:1372893

Popescu, Bogdan F. ^[1]; Frischer, Josa M. ^[2]; Webb, Samuel M. ^[3]; Tham, Mylyne ^[1]; Adiele, Reginald C. ^[1]; Robinson, Christopher A. ^[1]; Fitz-Gibbon, Patrick D. ^[4]; Weigand, Stephen D. ^[4]; Metz, Imke ^[5]; Nehzati, Susan ^[1]; George, Graham N. ^[1]; Pickering, Ingrid J. ^[1]; Bruck, Wolfgang ^[5]; Hametner, Simon ^[6]; Lassmann, Hans ^[6]; Parisi, Joseph E. ^[4]; Yong, Guo ^[4]; Lucchinetti, Claudia F. ^[4]

Univ. of Saskatchewan, Saskatoon (Canada)
Medical Univ. Vienna, Vienna (Austria)
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Mayo Clinic, Rochester, MN (United States)
Univ. of Gottingen, Gottingen (Germany)
Medical Univ. of Vienna, Vienna (Austria)

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), High Energy Physics (HEP)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1372893

Journal Information:: Acta Neuropathologica, Vol. 134, Issue 1; ISSN 0001-6322

Publisher:: SpringerCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 75 works

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Zinc Signals and Immunity Maywald, Martina; Weßels, Inga; Rink, Lothar RWTH Aachen University https://doi.org/10.18154/rwth-2017-10705	text	January 2017
Zinc as a Gatekeeper of Immune Function Wessels, Inga; Maywald, Martina; Rink, Lothar RWTH Aachen University https://doi.org/10.18154/rwth-2018-221110	text	January 2017
The Intracellular Free Zinc Level Is Vital for Treg Function and a Feasible Tool to Discriminate between Treg and Activated Th Cells Maywald, Martina; Wang, Fudi; Rink, Lothar RWTH Aachen University https://doi.org/10.18154/rwth-conv-236961	text	January 2018
Early MRI predictors of prognosis in multiple sclerosis Davda, Nikunj; Tallantyre, Emma; Robertson, Neil P. Journal of Neurology, Vol. 266, Issue 12 https://doi.org/10.1007/s00415-019-09589-2	journal	November 2019

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60 APPLIED LIFE SCIENCES
59 BASIC BIOLOGICAL SCIENCES
synchrotron
iron
zinc
multiple sclerosis
oligodendrocyte
smoldering lesion
shadow plaque
astrocyte
remyelination

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