Why Is Wallerian Degeneration in the CNS So Slow?

Vargas, Mauricio E.; Barres, Ben A.

doi:10.1146/annurev.neuro.30.051606.094354

Cited by 421 publications

(410 citation statements)

References 203 publications

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“…3 Vargas et al found that myelin degradation in the central nervous system (CNS) is slow, probably because oligodendrocytes cannot phagocytose myelin debris, and there is no influx of peripheral macrophages in the CNS to speed up the degradation process. 31 This supports our finding of increasing ADC values evolving into the chronic phase. As the posterior truncus is especially enriched in large myelinated fibers, TBI-induced demyelination may have larger impact in this region, and hence lead to the faster and more notable increase in ADC values in region IV.…”

Section: Neuropathological Origin Of Increased Adc Values In Differensupporting

confidence: 90%

A Longitudinal Magnetic Resonance Imaging Study of the Apparent Diffusion Coefficient Values in Corpus Callosum during the First Year after Traumatic Brain Injury

Moen

Håberg

Skandsen

et al. 2014

Journal of Neurotrauma

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The objective of this study was to explore the evolution of apparent diffusion coefficient (ADC) values in magnetic resonance imaging (MRI) in normal-appearing tissue of the corpus callosum during the 1st year after traumatic brain injury (TBI), and relate findings to outcome. Fifty-seven patients (mean age 34 [range 11-63] years) with moderate to severe TBI were examined with diffusion weighted MRI at three time points (median 7 days, 3 and 12 months), and a sexand age-matched control group of 47 healthy individuals, were examined once. The corpus callosum was subdivided and the mean ADC values computed blinded in 10 regions of interests without any visible lesions in the ADC map. Outcome measures were Glasgow Outcome Scale Extended (GOSE) and neuropsychological domain scores at 12 months. We found a gradual increase of the mean ADC values during the 12 month follow-up, most evident in the posterior truncus (r = 0.19, p < 0.001). Compared with the healthy control group, we found higher mean ADC values in posterior truncus both at 3 months ( p = 0.021) and 12 months ( p = 0.003) post-injury. Patients with fluid-attenuated inversion recovery (FLAIR) lesions in the corpus callosum in the early MRI, and patients with disability (GOSE score £ 6) showed evidence of increased mean ADC values in the genu and posterior truncus at 12 months. Mean ADC values in posterior parts of the corpus callosum at 3 months predicted the sensory-motor function domain score ( p = 0.010-0.028). During the 1st year after moderate and severe TBI, we demonstrated a slowly evolving disruption of the microstructure in normal appearing corpus callosum in the ADC map, most evident in the posterior truncus. The mean ADC values were associated with both outcome and ability to perform speeded, complex sensory-motor action.

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Section: Neuropathological Origin Of Increased Adc Values In Differensupporting

confidence: 90%

A Longitudinal Magnetic Resonance Imaging Study of the Apparent Diffusion Coefficient Values in Corpus Callosum during the First Year after Traumatic Brain Injury

Moen

Håberg

Skandsen

et al. 2014

Journal of Neurotrauma

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“…Because Schwann cells are not found in the CNS and the blood-brain barrier prevents the entry of anti-CNS myelin antibodies into the distal white matter tracks, the injured CNS lacks the critical repair mechanisms available to the PNS. Our data therefore suggest the possibility that antibodies directed against CNS myelin, such as exogenously delivered anti-NogoA antibodies (7,24,25) or antibodies induced by CNS myelin immunization (26), promote CNS axon regeneration not only by neutralizing myelin inhibitors but, perhaps more importantly, by promoting myelin clearance. Indeed, opsonization by anti-NogoA antibodies could explain the greater apparent ability of the delivery of anti-NogoA antibodies to mediate regeneration than the genetic removal of NogoA (25).…”

Section: Discussionmentioning

confidence: 82%

“…Although peripheral myelin also contains inhibitors of axon regeneration, PNS myelin is rapidly cleared after injury, thereby permitting rapid axon regeneration (4)(5)(6). It is not known why the rates of clearance of PNS and CNS are so different (7).…”

mentioning

confidence: 99%

Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury

Vargas¹,

Watanabe²,

Singh³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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142

129

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Degenerating myelin inhibits axon regeneration and is rapidly cleared after peripheral (PNS) but not central nervous system (CNS) injury. To better understand mechanisms underlying rapid PNS myelin clearance, we tested the potential role of the humoral immune system. Here, we show that endogenous antibodies are required for rapid and robust PNS myelin clearance and axon regeneration. B-cell knockout JHD mice display a significant delay in macrophage influx, myelin clearance, and axon regeneration. Rapid clearance of myelin debris is restored in mutant JHD mice by passive transfer of antibodies from naïve WT mice or by an anti-PNS myelin antibody, but not by delivery of nonneural antibodies. We demonstrate that degenerating nerve tissue is targeted by preexisting endogenous antibodies that control myelin clearance by promoting macrophage entrance and phagocytic activity. These results demonstrate a role for immunoglobulin (Ig) in clearing damaged self during healing and suggest that the immune-privileged status of the CNS may contribute to failure of CNS myelin clearance and axon regeneration after injury.humoral immunity | nerve regeneration D uring the process of wound healing, rapid and efficient clearance of cellular debris is necessary for tissue regeneration (1). Myelin debris remains in white matter tracks years after an injury to the CNS in humans and primates (2, 3). The prolonged presence of myelin-associated inhibitors of axon regeneration is thought to contribute to the lack of recovery following CNS injury. Although peripheral myelin also contains inhibitors of axon regeneration, PNS myelin is rapidly cleared after injury, thereby permitting rapid axon regeneration (4-6). It is not known why the rates of clearance of PNS and CNS are so different (7).Antibodies, like other opsonins, coat exogenous debris and pathogens, thereby targeting them for clearance by phagocytes. The recognition of self antigens by natural antibodies produced by B1 cells is well documented (8). Although it is hypothesized that these antibodies may have a physiological role other than immune defense, their role in clearing necrotic cellular debris is not known (8). Therefore, we tested whether endogenous antibodies contribute to rapid removal of degenerating myelin after PNS injury, thereby promoting axon regeneration. ResultsAntibodies Accumulate in Sciatic Nerve After Injury. To investigate whether endogenous antibodies aid in removal of myelin debris, we first examined whether antibodies accumulate in peripheral nerves following injury. We compared nerve injury responses between WT and JHD mice, which have a targeted deletion of the JH locus that prevents VDJ recombination and the formation of mature B-cells and antibodies (9). Control and crushed sciatic nerves were obtained from WT and JHD mice and stained with anti-mouse Ig antibodies. Six days after crush injury, we observed a strong increase in immunoreactivity for Ig on degenerating myelin sheathes distal to the site of injury in WT but not in JHD nerves (Fig. S1A). To ...

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“…The breakdown of the myelin sheath is carried out by Schwann cells and invading macrophages (reviewed in Koeppen, 2004;Vargas and Barres, 2007). There is evidence that the contribution of macrophages to myelin clearance is modest during the first week or so after injury (Perry et al, 1995).…”

Section: Schwann Cell Dedifferentiation During Wallerian Degenerationmentioning

confidence: 99%

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

Jessen

Mirsky

2008

Glia

446

409

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Dedifferentiation of myelinating Schwann cells is a key feature of nerve injury and demyelinating neuropathies. We review recent evidence that this dedifferentiation depends on activation of specific intracellular signaling molecules that drive the dedifferentiation program. In particular, we discuss the idea that Schwann cells contain negative transcriptional regulators of myelination that functionally complement positive regulators such as Krox-20, and that myelination is therefore determined by a balance between two opposing transcriptional programs. Negative transcriptional regulators should be expressed prior to myelination, downregulated as myelination starts but reactivated as Schwann cells dedifferentiate following injury. The clearest evidence for a factor that works in this way relates to c-Jun, while other factors may include Notch, Sox-2, Pax-3, Id2, Krox-24, and Egr-3. The role of cell-cell signals such as neuregulin-1 and cytoplasmic signaling pathways such as the extracellular-related kinase (ERK)1/2 pathway in promoting dedifferentiation of myelinating cells is also discussed. We also review evidence that neurotrophin 3 (NT3), purinergic signaling, and nitric oxide synthase are involved in suppressing myelination. The realization that myelination is subject to negative as well as positive controls contributes significantly to the understanding of Schwann cell plasticity. Negative regulators are likely to have a major role during injury, because they promote the transformation of damaged nerves to an environment that fosters neuronal survival and axonal regrowth. In neuropathies, however, activation of these pathways is likely to be harmful because they may be key contributors to demyelination, a situation which would open new routes for clinical intervention. V V C 2008 Wiley-Liss, Inc.

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Why Is Wallerian Degeneration in the CNS So Slow?

Cited by 421 publications

References 203 publications

A Longitudinal Magnetic Resonance Imaging Study of the Apparent Diffusion Coefficient Values in Corpus Callosum during the First Year after Traumatic Brain Injury

A Longitudinal Magnetic Resonance Imaging Study of the Apparent Diffusion Coefficient Values in Corpus Callosum during the First Year after Traumatic Brain Injury

Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

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