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Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis / Owain, Howell

Journal of Neuropathology and Experimental Neurology, Volume: 69, Issue: 10, Pages: 1017 - 1033

Swansea University Author: Owain, Howell

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DOI (Published version): 10.1097/NEN.0b013e3181f3a5b1

Abstract

The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. Wedescribe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal...

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Published in: Journal of Neuropathology and Experimental Neurology
Published: 2010
Online Access: http://www.scopus.com/record/display.url?eid=2-s2.0-77957931759&origin=resultslist&sort=plf-f&src=s&st1=howell&st2=o.w&nlo=1&nlr=20&nls=&sid=942755C5CBB33656BBE96DCBEAC4A9AE.iqs8TDG0Wy6BURhzD3nFA%3a122&sot=anl&sdt=aut&sl=33&s=AU-ID%28%22Howell%2c+O.+W.%22+6602393502%29&relpos=8&relpos=8&searchTerm=AU-ID%28\%26quot%3BHowell%2C+O.+W.\%26quot%3B+6602393502%29
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spelling 2013-12-13T11:27:14.1871389 v2 14217 2013-02-11 Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 2013-02-11 BMS The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. Wedescribe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal-appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent ofparanodal axoglial (neurofascin-155/Caspr1) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction. Journal Article Journal of Neuropathology and Experimental Neurology 69 10 1017 1033 31 12 2010 2010-12-31 10.1097/NEN.0b013e3181f3a5b1 http://www.scopus.com/record/display.url?eid=2-s2.0-77957931759&amp;origin=resultslist&amp;sort=plf-f&amp;src=s&amp;st1=howell&amp;st2=o.w&amp;nlo=1&amp;nlr=20&amp;nls=&amp;sid=942755C5CBB33656BBE96DCBEAC4A9AE.iqs8TDG0Wy6BURhzD3nFA%3a122&amp;sot=anl&amp;sdt=aut&amp;sl=33&amp;s=AU-ID%28%22Howell%2c+O.+W.%22+6602393502%29&amp;relpos=8&amp;relpos=8&amp;searchTerm=AU-ID%28\%26quot%3BHowell%2C+O.+W.\%26quot%3B+6602393502%29 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2013-12-13T11:27:14.1871389 2013-02-11T18:26:29.7589275 Swansea University Medical School Medicine Owain Howell 0000-0003-2157-9157 1 Jon L Rundle 2 Anurag Garg 3 Masayuki Komada 4 Peter J Brophy 5 Richard Reynolds 6
title Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis
spellingShingle Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis
Owain, Howell
title_short Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis
title_full Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis
title_fullStr Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis
title_full_unstemmed Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis
title_sort Activated Microglia Mediate Axoglial Disruption That Contributes to Axonal Injury in Multiple Sclerosis
author_id_str_mv 58c995486fc93a242b987640b692db8c
author_id_fullname_str_mv 58c995486fc93a242b987640b692db8c_***_Owain, Howell
author Owain, Howell
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description The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. Wedescribe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal-appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent ofparanodal axoglial (neurofascin-155/Caspr1) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction.
published_date 2010-12-31T19:26:43Z
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