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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Journal of Neuroinflammation 1/2017

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

Zeitschrift:
Journal of Neuroinflammation > Ausgabe 1/2017
Autoren:
Shailender Singh, Tobias Dallenga, Anne Winkler, Shanu Roemer, Brigitte Maruschak, Heike Siebert, Wolfgang Brück, Christine Stadelmann
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12974-017-0831-8) contains supplementary material, which is available to authorized users.

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.
Zusatzmaterial
Additional file 1: NPY-Y1R+ axon undergoing Wallerian degeneration do not co-localize with hypophosphorylated and low-molecular-weight NF in EAE. Double-labeling fluorescent IHC reveals that NPY-Y1R+ degenerating axons are only rarely labeled with antibodies recognizing hypophosphorylated NF (SMI35) (A-C). No colocalization is observed with the 68 kDa low-molecular-weight NF (D-F) in WT EAE lesional and perilesional tissue. Scale bars=(A-F) 100 μm. (JPG 343 kb)
12974_2017_831_MOESM1_ESM.jpg
Additional file 2: Axons undergoing Wallerian degeneration are at least in part myelinated in EAE lesions. No co-localization of NPY-Y1R immunoreactivity with myelin proteins, i.e., PLP (A-C), MOG (D-F), MAG (G-I), and CNPase (J-L) was observed by fluorescence double IHC in WT EAE mice, which further confirms that the antiserum against NPY-Y1R applied does not detect an antigen situated within the myelin sheath or myelin ovoids. Insets in (A-C) represent NPY-Y1R+ degenerating fiber(s) in largely intact myelinated tracts, as determined by anti-PLP IHC. Scale bars=(A-L) 200 μm; (insets A-C) 10 μm. (JPG 673 kb)
12974_2017_831_MOESM2_ESM.jpg
Additional file 3: NPY-Y1R IHC labels myelin ovoids typical of Wallerian degeneration in mouse sciatic nerve transection. Elongated, beaded NPY-Y1R+ (red, A) axonal structures surrounded by MBP+ myelin sheaths (green, B) are seen in longitudinal sections of mouse sciatic nerve 6 days after and distal to the transection (C, arrows). Oil-immersion magnification (×1000) revealed that NPY-Y1R+ axons were enwrapped with myelin (MBP) indicating myelin ovoid formation, typical of Wallerian degeneration (D-F). (p < 0.05; G). Scale bars=(A-C) 100 μm; (D-F) 20 μm. (JPG 1484 kb)
12974_2017_831_MOESM3_ESM.jpg
Additional file 4: Neuroaxonal regenerative markers are not co-expressed in axons undergoing Wallerian degeneration. Axonal structures immunopositive for GAP43 (A-C) and Synaptophysin (Syn) (D-F) did not co-localize with NPY-Y1R+ degenerating axons in WT EAE lesions by immunofluorescent double labeling. Syn expression was mostly limited to gray matter regions of the SC in WT EAE. Scale bars=(A-F) 100 μm. (JPG 816 kb)
12974_2017_831_MOESM4_ESM.jpg
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