Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions.
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. Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.
Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, 701 Queen Street, Saskatoon, SK, S7N 5E5, Canada. bogdan.popescu@usask.ca.|Cameco MS Neuroscience Research Center, University of Saskatchewan, 701 Queen Street, Saskatoon City Hospital, Rm 5800, Saskatoon, SK, S7K 0M7, Canada. bogdan.popescu@usask.ca.
Bogdan F
BF
Popescu
Department of Neurosurgery, Medical University Vienna, Vienna, Austria.
Josa M
JM
Frischer
Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
Samuel M
SM
Webb
Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, 701 Queen Street, Saskatoon, SK, S7N 5E5, Canada.|Cameco MS Neuroscience Research Center, University of Saskatchewan, 701 Queen Street, Saskatoon City Hospital, Rm 5800, Saskatoon, SK, S7K 0M7, Canada.
Mylyne
M
Tham
Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, 701 Queen Street, Saskatoon, SK, S7N 5E5, Canada.|Cameco MS Neuroscience Research Center, University of Saskatchewan, 701 Queen Street, Saskatoon City Hospital, Rm 5800, Saskatoon, SK, S7K 0M7, Canada.
Reginald C
RC
Adiele
Department of Pathology and Laboratory Medicine, Saskatoon Health Region/College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Christopher A
CA
Robinson
Department of Health Sciences Research, Mayo Clinic, College of Medicine, Rochester, MN, USA.
Patrick D
PD
Fitz-Gibbon
Department of Health Sciences Research, Mayo Clinic, College of Medicine, Rochester, MN, USA.
Stephen D
SD
Weigand
Department of Neuropathology, University of Göttingen, Göttingen, Germany.
Imke
I
Metz
Molecular and Environmental Science Research Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, Canada.
Susan
S
Nehzati
Molecular and Environmental Science Research Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, Canada.|Toxicology Center, University of Saskatchewan, Saskatoon, Canada.|Department of Chemistry, University of Saskatchewan, Saskatoon, Canada.
Graham N
GN
George
Molecular and Environmental Science Research Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, Canada.|Toxicology Center, University of Saskatchewan, Saskatoon, Canada.|Department of Chemistry, University of Saskatchewan, Saskatoon, Canada.
Ingrid J
IJ
Pickering
Department of Neuropathology, University of Göttingen, Göttingen, Germany.
Wolfgang
W
Brück
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Simon
S
Hametner
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Hans
H
Lassmann
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Joseph E
JE
Parisi
Department of Neurology, Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
Guo
G
Yong
Department of Neurology, Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA. clucchinetti@mayo.edu.
Claudia F
CF
Lucchinetti
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D001923:Brain Chemistry; D005260:Female; D005293:Ferritins / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000032:analysis*; D008264:Macrophages / Q000737:chemistry / Q000473:pathology; D008297:Male; D017628:Microglia / Q000737:chemistry / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D000074586:Remyelination; D055815:Young Adult; D015032:Zinc / Q000032:analysis*
D005293:Ferritins; D007501:Iron; D015032:Zinc
Astrocyte; Iron; Multiple sclerosis; Oligodendrocyte; Remyelination; Shadow plaque; Smoldering lesion; Synchrotron; Zinc