Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with episodes of inflammatory demyelination and remyelination. While remyelination has been linked with functional recovery in MS patients, there is evidence of ongoing tissue damage despite complete myelin...
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doaj-d0c5a8f42ac54b1498bcc32084c4d86c2021-06-11T05:12:17ZengElsevierNeurobiology of Disease1095-953X2021-07-01155105371Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficitsJiangshan Zhan0Florian Nepomuk Fegg1Hannes Kaddatz2Sebastian Rühling3Julia Frenz4Bernd Denecke5Sandra Amor6Peter Ponsaerts7Tanja Hochstrasser8Markus Kipp9Institute of Anatomy, Rostock University Medical Center, Rostock, Germany; Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, GermanyInstitute of Anatomy, Rostock University Medical Center, Rostock, Germany; Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, GermanyInstitute of Anatomy, Rostock University Medical Center, Rostock, Germany; Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, GermanyInstitute of Anatomy, Rostock University Medical Center, Rostock, Germany; Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, GermanyInstitute of Anatomy, Rostock University Medical Center, Rostock, Germany; Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, GermanyInterdisciplinary Center for Clinical Research Aachen (IZKF Aachen), RWTH Aachen University, Aachen, GermanyDepartment of Pathology, Amsterdam UMC, VUMC site, Amsterdam, the Netherlands; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UKFaculty of Medicine and Health Sciences, University of Antwerp, Antwerp 2610, BelgiumDepartment of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, GermanyInstitute of Anatomy, Rostock University Medical Center, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, Gelsheimer Strasse 20, 18147 Rostock, Germany; Corresponding author at: Gertrudenstrasse 9, 18057 Rostock; Rostock University Medical Center, Institute of Anatomy, GermanyMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with episodes of inflammatory demyelination and remyelination. While remyelination has been linked with functional recovery in MS patients, there is evidence of ongoing tissue damage despite complete myelin repair. In this study, we investigated the long-term consequences of an acute demyelinating white matter CNS lesion. For this purpose, acute demyelination was induced by 5-week-cuprizone intoxication in male C57BL/6 J mice, and the tissues were examined after a 7-month recovery period. While myelination and oligodendrocyte densities appeared normal, ongoing axonal degeneration and glia cell activation were found in the remyelinated corpus callosum. Neuropathologies were paralleled by subtle gait abnormalities evaluated using DigiGait™ high speed ventral plane videography. Gene array analyses revealed increased expression levels of various inflammation related genes, among protein kinase c delta (PRKCD). Immunofluorescence stains revealed predominant microglia/macrophages PRKCD expression in both, cuprizone tissues and post-mortem MS lesions. These results support the hypothesis that chronic microglia/macrophages driven tissue injury represents a key aspect of progressive neurodegeneration and functional decline in MS.http://www.sciencedirect.com/science/article/pii/S0969996121001200Multiple sclerosisGliosisAxonal damageRemyelinationProtein kinase c delta |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jiangshan Zhan Florian Nepomuk Fegg Hannes Kaddatz Sebastian Rühling Julia Frenz Bernd Denecke Sandra Amor Peter Ponsaerts Tanja Hochstrasser Markus Kipp |
spellingShingle |
Jiangshan Zhan Florian Nepomuk Fegg Hannes Kaddatz Sebastian Rühling Julia Frenz Bernd Denecke Sandra Amor Peter Ponsaerts Tanja Hochstrasser Markus Kipp Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits Neurobiology of Disease Multiple sclerosis Gliosis Axonal damage Remyelination Protein kinase c delta |
author_facet |
Jiangshan Zhan Florian Nepomuk Fegg Hannes Kaddatz Sebastian Rühling Julia Frenz Bernd Denecke Sandra Amor Peter Ponsaerts Tanja Hochstrasser Markus Kipp |
author_sort |
Jiangshan Zhan |
title |
Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits |
title_short |
Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits |
title_full |
Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits |
title_fullStr |
Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits |
title_full_unstemmed |
Focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits |
title_sort |
focal white matter lesions induce long-lasting axonal degeneration, neuroinflammation and behavioral deficits |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2021-07-01 |
description |
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with episodes of inflammatory demyelination and remyelination. While remyelination has been linked with functional recovery in MS patients, there is evidence of ongoing tissue damage despite complete myelin repair. In this study, we investigated the long-term consequences of an acute demyelinating white matter CNS lesion. For this purpose, acute demyelination was induced by 5-week-cuprizone intoxication in male C57BL/6 J mice, and the tissues were examined after a 7-month recovery period. While myelination and oligodendrocyte densities appeared normal, ongoing axonal degeneration and glia cell activation were found in the remyelinated corpus callosum. Neuropathologies were paralleled by subtle gait abnormalities evaluated using DigiGait™ high speed ventral plane videography. Gene array analyses revealed increased expression levels of various inflammation related genes, among protein kinase c delta (PRKCD). Immunofluorescence stains revealed predominant microglia/macrophages PRKCD expression in both, cuprizone tissues and post-mortem MS lesions. These results support the hypothesis that chronic microglia/macrophages driven tissue injury represents a key aspect of progressive neurodegeneration and functional decline in MS. |
topic |
Multiple sclerosis Gliosis Axonal damage Remyelination Protein kinase c delta |
url |
http://www.sciencedirect.com/science/article/pii/S0969996121001200 |
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