title: Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis.
abstract: Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. Here, we assessed the amount of Wallerian degeneration in brain tissue of multiple sclerosis patients in relation to demyelinating lesion activity and asked whether a transient blockade of Wallerian degeneration decreases axonal loss and clinical disability in a mouse model of inflammatory demyelination.
  
  
  
  Wallerian degeneration and acute axonal damage were determined immunohistochemically in the periplaque white matter of multiple sclerosis patients with early actively demyelinating lesions, chronic active lesions, and inactive lesions. Furthermore, we studied the effects of Wallerian degeneration blockage on clinical severity, inflammatory pathology, acute axonal damage, and long-term axonal loss in experimental autoimmune encephalomyelitis using Wallerian degeneration slow (WldS) mutant mice.
  
  
  
  The highest numbers of axons undergoing Wallerian degeneration were found in the perilesional white matter of multiple sclerosis patients early in the disease course and with actively demyelinating lesions. Furthermore, Wallerian degeneration was more abundant in patients harboring chronic active as compared to chronic inactive lesions. No co-localization of neuropeptide Y-Y1 receptor, a bona fide immunohistochemical marker of Wallerian degeneration, with amyloid precursor protein, frequently used as an indicator of acute axonal transport disturbance, was observed in human and mouse tissue, indicating distinct axon-degenerative processes. Experimentally, a delay of Wallerian degeneration, as observed in WldSmice, did not result in a reduction of clinical disability or acute axonal damage in experimental autoimmune encephalomyelitis, further supporting that acute axonal damage as reflected by axonal transport disturbances does not share common molecular mechanisms with Wallerian degeneration. Furthermore, delaying Wallerian degeneration did not result in a net rescue of axons in late lesion stages of experimental autoimmune encephalomyelitis.
  
  
  
  Our data indicate that in multiple sclerosis, ongoing demyelination in focal lesions is associated with axonal degeneration in the perilesional white matter, supporting a role for focal pathology in diffuse white matter damage. Also, our results suggest that interfering with Wallerian degeneration in inflammatory demyelination does not suffice to prevent acute axonal damage and finally axonal loss.
authors.affiliation: Institute of Neuropathology, University Medical Center, Göttingen, Germany.
authors.forename: Shailender
authors.initials: S
authors.lastname: Singh
authors.affiliation: Institute of Neuropathology, University Medical Center, Göttingen, Germany.|Cellular Microbiology, Research Center Borstel, Borstel, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Dallenga
authors.affiliation: Institute of Neuropathology, University Medical Center, Göttingen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Winkler
authors.affiliation: Institute of Neuropathology, University Medical Center, Göttingen, Germany.|Department of Neurology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Shanu
authors.initials: S
authors.lastname: Roemer
authors.affiliation: Institute of Neuropathology, University Medical Center, Göttingen, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Maruschak
authors.affiliation: Institute of Neuropathology, University Medical Center, Göttingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Siebert
authors.affiliation: Institute of Neuropathology, University Medical Center, Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Institute of Neuropathology, University Medical Center, Göttingen, Germany. cstadelmann@med.uni-goettingen.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
mesh_terms: D000328:Adult; D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000473:pathology*; D001921:Brain / Q000378:metabolism*; D006233:Persons with Disabilities; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications* / Q000473:pathology*; D009185:Myelin Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012585:Sciatica / Q000473:pathology; D020521:Stroke / Q000473:pathology; D014855:Wallerian Degeneration / Q000209:etiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; C442580:Wld protein, mouse
keywords: Axonal damage; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Wallerian degeneration; Wld S