Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Abstract

Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de‐ and remyelination, we employed cuprizone‐ and focal lysolecithin‐induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP‐ and SMI32‐ positive damaged axons and the density of SMI31‐positive and silver impregnated preserved axons. Early de‐ and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult.

Amyloid precursor protein and amyloid precursor‐like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons

“…Our observations suggest that APP has a greater role in remyelination rather than in myelin maintenance. This notion is supported by the data showing APP expression was undetectable in healthy axons but accumulated in damaged axons and was significantly upregulated during the early remyelination but decreased gradually during myelination as the proportion of myelinated axons increased (Schultz et al, ). Other evidence supporting APP having a critical role in axon remyelination is obtained in reports showing high levels of APP immunoreactivity in premyelinating oligodendrocyte expressing cells and in demyelinating lesions (Ferguson et al, ; Gehrmann, Banati, Cuzner, Kreutzberg, & Newcombe, ).…”

White matter plasticity and maturation in human cognition

“…Post‐mortem MS studies have shown myelin and axonal injury within lesions: However, axons appear to be preserved in remyelinated areas (Schultz et al, ): Crucially, if axons are not remyelinated, axonal degeneration occurs (Lee, Biemond, & Petratos, ; Simons, Misgeld, & Kerschensteiner, ; Singh et al, ). Post‐mortem data from MOG lesions demonstrated demyelination with partial axonal preservation (Zhou et al, ).…”

CSF β-amyloid predicts prognosis in patients with multiple sclerosis

“…On the other, CSF Aβ reduction could depend on APP deposition around injured axons, although there is no evidence of Aβ deposition in MS plaques. Recent studies showed that APP-expressing axons are partially myelinated, suggesting that acute axonal damage may, at least partially, occur independently from demyelination 24 . In other words, dysregulation of BACE1 and NRG1 might represent the myelin repair processes, while APP expression might be regarded as a biomarker of acute axonal injury.…”