Abstract

BackgroundAxonal 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.MethodsWallerian 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.ResultsThe 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 WldS 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.ConclusionsOur 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.

Highlights

  • Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis

  • Using neuropeptide Y-Y1 receptor (NPY-Y1R) immunohistochemistry, Wallerian degeneration was quantified in areas of periplaque white matter (PPWM) brain tissue from 31 multiple sclerosis patients

  • The present study provides evidence that axonal degeneration in multiple sclerosis is closely related to the occurrence of focal axonal transport disturbances, to focal demyelination and to phagocyte activation

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Summary

Introduction

Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. 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. As visualized by the accumulation of anterogradely transported proteins such as amyloid precursor protein (APP) and synaptophysin, are often used as indicators of “acute axonal damage,” and the density of APP-positive axonal profiles is highest in the earliest stages of multiple sclerosis lesion formation [2, 11, 12]. Axons with transport disturbance are present at relatively high density in the rims of chronic active, smoldering lesions and may be found in the NAWM [2, 13, 14]. Correlations of APP-positive axonal profiles with the density of macrophages have been repeatedly shown for early lesions; in chronic disease, a correlation with T cells was observed [2, 14,15,16]

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