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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis

Authors: Shailender Singh, Tobias Dallenga, Anne Winkler, Shanu Roemer, Brigitte Maruschak, Heike Siebert, Wolfgang Brück, Christine Stadelmann

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

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.

Methods

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 (Wld S ) mutant mice.

Results

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 Wld S mice, 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.

Conclusions

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.
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Literature
1.
De Stefano N, Matthews PM, Antel JP, Preul M, Francis G, Arnold DL. Chemical pathology of acute demyelinating lesions and its correlation with disability. Ann Neurol. 1995;38:901–9.CrossRefPubMed
2.
Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain. 1997;120(Pt 3):393–9.CrossRefPubMed
3.
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278–85.CrossRefPubMed
4.
Losseff NA, Webb SL, O'Riordan JI, Page R, Wang L, Barker GJ, Tofts PS, McDonald WI, Miller DH, Thompson AJ. Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain. 1996;119(Pt 3):701–8.CrossRefPubMed
5.
Tallantyre EC, Bo L, Al-Rawashdeh O, Owens T, Polman CH, Lowe JS, Evangelou N. Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult Scler. 2010;16:406–11.CrossRefPubMed
6.
Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14:183–93.CrossRefPubMed
7.
Kearney H, Miller DH, Ciccarelli O. Spinal cord MRI in multiple sclerosis—diagnostic, prognostic and clinical value. Nat Rev Neurol. 2015;11:327–38.CrossRefPubMed
8.
Tallantyre EC, Bo L, Al-Rawashdeh O, Owens T, Polman CH, Lowe J, Evangelou N. Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease. Brain. 2009;132:1190–9.CrossRefPubMed
9.
10.
Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med. 2011;17:495–9.CrossRefPubMed
11.
Gentleman SM, Nash MJ, Sweeting CJ, Graham DI, Roberts GW. Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett. 1993;160:139–44.CrossRefPubMed
12.
Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain. 2002;125:2202–12.CrossRefPubMed
13.
Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128:2705–12.CrossRefPubMed
14.
Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175–89.CrossRefPubMedPubMedCentral
15.
Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain. 2000;123(Pt 6):1174–83.CrossRefPubMed
16.
Pfeifenbring S, Bunyan RF, Metz I, Rover C, Huppke P, Gartner J, Lucchinetti CF, Bruck W. Extensive acute axonal damage in pediatric multiple sclerosis lesions. Ann Neurol. 2015;77:655–67.CrossRefPubMedPubMedCentral
17.
Sorbara CD, Wagner NE, Ladwig A, Nikic I, Merkler D, Kleele T, Marinkovic P, Naumann R, Godinho L, Bareyre FM, et al. Pervasive axonal transport deficits in multiple sclerosis models. Neuron. 2014;84:1183–90.CrossRefPubMed
18.
Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol. 2002;1:232–41.CrossRefPubMed
19.
Haider L, Fischer MT, Frischer JM, Bauer J, Hoftberger R, Botond G, Esterbauer H, Binder CJ, Witztum JL, Lassmann H. Oxidative damage in multiple sclerosis lesions. Brain. 2011;134:1914–24.CrossRefPubMedPubMedCentral
20.
Kerschensteiner M, Schwab ME, Lichtman JW, Misgeld T. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nat Med. 2005;11:572–7.CrossRefPubMed
21.
Marinkovic P, Reuter MS, Brill MS, Godinho L, Kerschensteiner M, Misgeld T. Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2012;109:4296–301.CrossRefPubMedPubMedCentral
22.
Kutzelnigg A, Lassmann H. Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handb Clin Neurol. 2014;122:15–58.CrossRefPubMed
23.
Bruck W, Porada P, Poser S, Rieckmann P, Hanefeld F, Kretzschmar HA, Lassmann H. Monocyte/macrophage differentiation in early multiple sclerosis lesions. Ann Neurol. 1995;38:788–96.CrossRefPubMed
24.
Schirmer L, Albert M, Buss A, Schulz-Schaeffer WJ, Antel JP, Bruck W, Stadelmann C. Substantial early, but nonprogressive neuronal loss in multiple sclerosis (MS) spinal cord. Ann Neurol. 2009;66:698–704.CrossRefPubMed
25.
Bruck W, Bitsch A, Kolenda H, Bruck Y, Stiefel M, Lassmann H. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol. 1997;42:783–93.CrossRefPubMed
26.
Kaneko S, Wang J, Kaneko M, Yiu G, Hurrell JM, Chitnis T, Khoury SJ, He Z. Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models. J Neurosci. 2006;26:9794–804.CrossRefPubMed
27.
Takada H, Yuasa S, Araki T. Demyelination can proceed independently of axonal degradation during Wallerian degeneration in wlds mice. Eur J Neurosci. 2011;34:531–7.CrossRefPubMed
28.
Nogai A, Siffrin V, Bonhagen K, Pfueller CF, Hohnstein T, Volkmer-Engert R, Bruck W, Stadelmann C, Kamradt T. Lipopolysaccharide injection induces relapses of experimental autoimmune encephalomyelitis in nontransgenic mice via bystander activation of autoreactive CD4+ cells. J Immunol. 2005;175:959–66.CrossRefPubMed
29.
Maimone D, Gregory S, Arnason BG, Reder AT. Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J Neuroimmunol. 1991;32:67–74.CrossRefPubMed
30.
31.
Dziedzic T, Metz I, Dallenga T, Konig FB, Muller S, Stadelmann C, Bruck W. Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis. Brain Pathol. 2010;20:976–85.PubMed
32.
Singh S, Metz I, Amor S, van der Valk P, Stadelmann C, Bruck W. Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. Acta Neuropathol. 2013;125:595–608.CrossRefPubMedPubMedCentral
33.
Vargas ME, Barres BA. Why is Wallerian degeneration in the CNS so slow? Annu Rev Neurosci. 2007;30:153–79.CrossRefPubMed
34.
Perry VH, Brown MC, Lunn ER. Very slow retrograde and wallerian degeneration in the CNS of C57BL/Ola mice. Eur J Neurosci. 1991;3:102–5.CrossRefPubMed
35.
Siebert H, Bruck W. The role of cytokines and adhesion molecules in axon degeneration after peripheral nerve axotomy: a study in different knockout mice. Brain Res. 2003;960:152–6.CrossRefPubMed
36.
Waxman SG, Black JA, Ransom BR, Stys PK. Protection of the axonal cytoskeleton in anoxic optic nerve by decreased extracellular calcium. Brain Res. 1993;614:137–45.CrossRefPubMed
37.
George EB, Glass JD, Griffin JW. Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels. J Neurosci. 1995;15:6445–52.PubMed
38.
Mack TG, Reiner M, Beirowski B, Mi W, Emanuelli M, Wagner D, Thomson D, Gillingwater T, Court F, Conforti L, et al. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat Neurosci. 2001;4:1199–206.CrossRefPubMed
39.
Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol. 2000;48:893–901.CrossRefPubMed
40.
De Stefano N, Narayanan S, Francis SJ, Smith S, Mortilla M, Tartaglia MC, Bartolozzi ML, Guidi L, Federico A, Arnold DL. Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch Neurol. 2002;59:1565–71.CrossRefPubMed
41.
Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A, Martinelli V, Grossman RI, Scotti G, Comi G, Falini A. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain. 2003;126:433–7.CrossRefPubMed
42.
Vogt J, Paul F, Aktas O, Muller-Wielsch K, Dorr J, Dorr S, Bharathi BS, Glumm R, Schmitz C, Steinbusch H, et al. Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis. Ann Neurol. 2009;66:310–22.CrossRefPubMed
43.
Ellwardt E, Zipp F. Molecular mechanisms linking neuroinflammation and neurodegeneration in MS. Exp Neurol. 2014;262 Pt A:8–17.CrossRefPubMed
44.
Lubinska L. Patterns of Wallerian degeneration of myelinated fibres in short and long peripheral stumps and in isolated segments of rat phrenic nerve. Interpretation of the role of axoplasmic flow of the trophic factor. Brain Res. 1982;233:227–40.CrossRefPubMed
45.
Tsao JW, Brown MC, Carden MJ, McLean WG, Perry VH. Loss of the compound action potential: an electrophysiological, biochemical and morphological study of early events in axonal degeneration in the C57BL/Ola mouse. Eur J Neurosci. 1994;6:516–24.CrossRefPubMed
46.
Griffin JW, George EB, ST H, Glass JD. Axonal degeneration and disorders of the axonal cytoskeleton. In: Waxman SG, Kocsis JD, Stys PK, editors. The axon: structure, function and pathophysiology. NY: Oxford University Press; 1995. p. 3750–90.
47.
48.
Tsao JW, George EB, Griffin JW. Temperature modulation reveals three distinct stages of Wallerian degeneration. J Neurosci. 1999;19:4718–26.PubMed
49.
50.
Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci U S A. 2004;101:8168–73.CrossRefPubMedPubMedCentral
51.
Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, Vincent A, Fugger L. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med. 2007;13:1483–9.CrossRefPubMed
52.
Schattling B, Steinbach K, Thies E, Kruse M, Menigoz A, Ufer F, Flockerzi V, Bruck W, Pongs O, Vennekens R, et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med. 2012;18:1805–11.CrossRefPubMed
53.
Adalbert R, Morreale G, Paizs M, Conforti L, Walker SA, Roderick HL, Bootman MD, Siklos L, Coleman MP. Intra-axonal calcium changes after axotomy in wild-type and slow Wallerian degeneration axons. Neuroscience. 2012;225:44–54.CrossRefPubMed
54.
Avery MA, Rooney TM, Pandya JD, Wishart TM, Gillingwater TH, Geddes JW, Sullivan PG, Freeman MR. WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. Curr Biol. 2012;22:596–600.CrossRefPubMedPubMedCentral
55.
O'Donnell KC, Vargas ME, Sagasti A. WldS and PGC-1alpha regulate mitochondrial transport and oxidation state after axonal injury. J Neurosci. 2013;33:14778–90.CrossRefPubMedPubMedCentral
56.
Breckwoldt MO, Pfister FM, Bradley PM, Marinkovic P, Williams PR, Brill MS, Plomer B, Schmalz A, St Clair DK, Naumann R, et al. Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo. Nat Med. 2014;20:555–60.CrossRefPubMed
57.
Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol. 2014;10:225–38.CrossRefPubMed
58.
Prineas JW, Kwon EE, Cho ES, Sharer LR, Barnett MH, Oleszak EL, Hoffman B, Morgan BP. Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol. 2001;50:646–57.CrossRefPubMed
59.
Mi W, Beirowski B, Gillingwater TH, Adalbert R, Wagner D, Grumme D, Osaka H, Conforti L, Arnhold S, Addicks K, et al. The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice. Brain. 2005;128:405–16.CrossRefPubMed
60.
Beirowski B, Nogradi A, Babetto E, Garcia-Alias G, Coleman MP. Mechanisms of axonal spheroid formation in central nervous system Wallerian degeneration. J Neuropathol Exp Neurol. 2010;69:455–72.CrossRefPubMed
61.
Glass JD, Brushart TM, George EB, Griffin JW. Prolonged survival of transected nerve fibres in C57BL/Ola mice is an intrinsic characteristic of the axon. J Neurocytol. 1993;22:311–21.CrossRefPubMed
62.
Raff MC, Whitmore AV, Finn JT. Axonal self-destruction and neurodegeneration. Science. 2002;296:868–71.CrossRefPubMed
63.
Wright GJ, Cherwinski H, Foster-Cuevas M, Brooke G, Puklavec MJ, Bigler M, Song Y, Jenmalm M, Gorman D, McClanahan T, et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J Immunol. 2003;171:3034–46.CrossRefPubMed
64.
Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290:1768–71.CrossRefPubMed
65.
Chitnis T, Imitola J, Wang Y, Elyaman W, Chawla P, Sharuk M, Raddassi K, Bronson RT, Khoury SJ. Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration. Am J Pathol. 2007;170:1695–712.CrossRefPubMedPubMedCentral
66.
Coleman M. Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci. 2005;6:889–98.CrossRefPubMed
67.
Barrientos SA, Martinez NW, Yoo S, Jara JS, Zamorano S, Hetz C, Twiss JL, Alvarez J, Court FA. Axonal degeneration is mediated by the mitochondrial permeability transition pore. J Neurosci. 2011;31:966–78.CrossRefPubMedPubMedCentral
68.
Stirling DP, Cummins K, Wayne Chen SR, Stys P. Axoplasmic reticulum Ca(2+) release causes secondary degeneration of spinal axons. Ann Neurol. 2014;75:220–9.CrossRefPubMed
69.
Walker MW, Ewald DA, Perney TM, Miller RJ. Neuropeptide Y modulates neurotransmitter release and Ca2+ currents in rat sensory neurons. J Neurosci. 1988;8:2438–46.PubMed
70.
Perney TM, Miller RJ. Two different G-proteins mediate neuropeptide Y and bradykinin-stimulated phospholipid breakdown in cultured rat sensory neurons. J Biol Chem. 1989;264:7317–27.PubMed
71.
Dumont Y, Martel JC, Fournier A, St-Pierre S, Quirion R. Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues. Prog Neurobiol. 1992;38:125–67.CrossRefPubMed
72.
Wahlestedt C, Reis DJ. Neuropeptide Y-related peptides and their receptors—are the receptors potential therapeutic drug targets? Annu Rev Pharmacol Toxicol. 1993;33:309–52.CrossRefPubMed
73.
Brumovsky PR, Shi TJ, Matsuda H, Kopp J, Villar MJ, Hokfelt T. NPY Y1 receptors are present in axonal processes of DRG neurons. Exp Neurol. 2002;174:1–10.CrossRefPubMed
74.
Obata K, Yamanaka H, Dai Y, Mizushima T, Fukuoka T, Tokunaga A, Noguchi K. Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats. Eur J Neurosci. 2004;20:2881–95.CrossRefPubMed
75.
Wrzos C, Winkler A, Metz I, Kayser DM, Thal DR, Wegner C, Bruck W, Nessler S, Bennett JL, Stadelmann C. Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions. Acta Neuropathol. 2014;127:523–38.CrossRefPubMed
76.
Matthieu JM, Waehneldt TV, Eschmann N. Myelin-associated glycoprotein and myelin basic protein are present in central and peripheral nerve myelin throughout phylogeny. Neurochem Int. 1986;8:521–6.CrossRefPubMed
77.
Radzun HJ, Hansmann ML, Heidebrecht HJ, Bodewadt-Radzun S, Wacker HH, Kreipe H, Lumbeck H, Hernandez C, Kuhn C, Parwaresch MR. Detection of a monocyte/macrophage differentiation antigen in routinely processed paraffin-embedded tissues by monoclonal antibody Ki-M1P. Lab Invest. 1991;65:306–15.PubMed
78.
Nacken W, Sopalla C, Propper C, Sorg C, Kerkhoff C. Biochemical characterization of the murine S100A9 (MRP14) protein suggests that it is functionally equivalent to its human counterpart despite its low degree of sequence homology. Eur J Biochem. 2000;267:560–5.CrossRefPubMed
Metadata
Title
Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis
Authors
Shailender Singh
Tobias Dallenga
Anne Winkler
Shanu Roemer
Brigitte Maruschak
Heike Siebert
Wolfgang Brück
Christine Stadelmann
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0831-8

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