Late motor decline after accomplished remyelination: Impact for progressive multiple sclerosis

Manrique-Hoyos, Natalia; Jürgens, Tanja; Grønborg, Mads; Kreutzfeldt, Mario; Schedensack, Mariann; Kuhlmann, Tanja; Schrick, Christina; Brück, Wolfgang; Urlaub, Henning; Simons, Mikael; Merkler, Doron

doi:10.1002/ana.22681

Cited by 93 publications

(72 citation statements)

References 76 publications

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“…Acute axonal damage decreased continuously during recovery presumably in part because of rapid and efficient oligodendrocyte differentiation and remyelination. However, acute axonal damage (∼9 APP + axons/mm 2 ) was shown to still occur after long‐term remyelination (28 weeks) (Manrique‐Hoyos et al, 2012). The axonal damage, which was evaluated after one (median 163.3 APP + axons/mm 2 ) or three (median 129.2 APP + axons/mm 2 ) weeks of remyelination in the present work, was much higher than the axonal damage observed in the study of Manrique‐Hoyos and colleagues, indicating that axonal damage is more prevalent early after cuprizone‐diet cessation.…”

Section: Discussionmentioning

confidence: 99%

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

Schultz

Meer

Wrzos

et al. 2017

Glia

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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.

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Section: Discussionmentioning

confidence: 99%

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

Schultz

Meer

Wrzos

et al. 2017

Glia

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“…Our observation that young zebrafish have normal thickness of myelin but still short internodes after remyelination leads us to suggest that myelin thickness and internodal length are controlled by different mechanisms. Thin myelin and short internodes may increase the vulnerability of remyelinated axons to neurodegeneration in the longer term [72,8] which is relevant in multiple sclerosis pathology to avoid progressive disability accumulation.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age

Münzel

Becker

et al. 2014

acta neuropathol commun

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Introduction: In the human demyelinating central nervous system (CNS) disease multiple sclerosis, remyelination promotes recovery and limits neurodegeneration, but this is inefficient and always ultimately fails. Furthermore, these regenerated myelin sheaths are thinner and shorter than the original, leaving the underlying axons potentially vulnerable. In rodent models, CNS remyelination is more efficient, so that in young animals (but not old) the number of myelinated axons is efficiently restored to normal, but in both young and old rodents, regenerated myelin sheaths are still short and thin. The reasons for these differences in remyelination efficiency, the thinner remyelinated myelin sheaths compared to developmental myelin and the subsequent effect on the underlying axon are unclear. We studied CNS remyelination in the highly regenerative adult zebrafish (Danio rerio), to better understand mechanisms of what we hypothesised would be highly efficient remyelination, and to identify differences to mammalian CNS remyelination, as larval zebrafish are increasingly used for high throughput screens to identify potential drug targets to improve myelination and remyelination. Results: We developed a novel method to induce a focal demyelinating lesion in adult zebrafish optic nerve with no discernible axonal damage, and describe the cellular changes over time. Remyelination is indeed efficient in both young and old adult zebrafish optic nerves, and at 4 weeks after demyelination, the number of myelinated axons is restored to normal, but internode lengths are short. However, unlike in rodents or in humans, in young zebrafish these regenerated myelin sheaths were of normal thickness, whereas in aged zebrafish, they were thin, and remained so even 3 months later. This inability to restore normal myelin thickness in remyelination with age was associated with a reduced macrophage/microglial response.

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“…Myelin contains 70%-80% lipids (by dry weight) and there is only a small set of proteins that reside within compacted myelin, of which myelin basic protein (MBP) and PLP are most abundant. Even if recent proteome studies have uncovered many more proteins within purified myelin fractions Ishii et al 2009;Dhaunchak et al 2010;Patzig et al 2011;Manrique-Hoyos et al 2012), it still holds true that the proteome of compact myelin is dominated by a few major, predominantly low molecular weight, and mostly myelin-specific proteins.…”

Section: Myelin Structurementioning

confidence: 99%

Oligodendrocytes: Myelination and Axonal Support

Simons

Nave

2015

Cold Spring Harb Perspect Biol

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463

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Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons. When Virchow analyzed the fine structure of the brain in the 1850s, he recognized that there were more cells within the "Nervenkitt" than astrocytes, but because of the imperfect staining methods, they remained obscure and were only named the "third element" (reviewed in Somjen 1988; Rosenbluth 1999). It was decades later that Pío del Río-Hortega (1921) applied a staining method involving silver carbonate, thereby shedding new light on the rest of the interstitial cells. These cells were found to contain numerous short processes and were named oligodendroglia and microglia. Defining features of oligodendrocytes were their small cell bodies filled with nuclei containing large amounts of chromatin, and their cellular extensions that lacked fibers but were filled with cytoplasmic granules (Fig. 1). When the tissue was optimally preserved, the silver impregnation uncovered a tremendous complexity of extensions (Fig. 1). del Río-Hortega was able to distinguish four types of oligodendrocytes ( Fig. 1): Type I cells generate many different myelin segments on small diameter axons in diverse orientations; type II cells are similar to type I in size and number, but myelin segments run in parallel to each other; type III oligodendrocytes ensheath fewer axons of larger diameter; and type IV oligodendrocytes have a cell body closely apposed to a single very large axon similar to Schwann cells. From the staining, it became clear that some of the processes run in parallel to axons and appeared to cover the axons with "myelin," a term that was introduced by Virchow already in

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Late motor decline after accomplished remyelination: Impact for progressive multiple sclerosis

Cited by 93 publications

References 76 publications

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

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

Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age

Oligodendrocytes: Myelination and Axonal Support

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