Genetically Induced Adult Oligodendrocyte Cell Death Is Associated with Poor Myelin Clearance, Reduced Remyelination, and Axonal Damage

Abstract

Loss of oligodendrocytes is a feature of many demyelinating diseases including multiple sclerosis. Here, we have established and characterized a novel model of genetically induced adult oligodendrocyte death. Specific primary loss of adult oligodendrocytes leads to a well defined and highly reproducible course of disease development that can be followed longitudinally by magnetic resonance imaging. Histological and ultrastructural analyses revealed progressive myelin vacuolation, in parallel to disease development that includes motor deficits, tremor, and ataxia. Myelin damage and clearance were associated with induction of oligodendrocyte precursor cell proliferation, albeit with some regional differences. Remyelination was present in the mildly affected corpus callosum. Consequences of acutely induced cell death of adult oligodendrocytes included secondary axonal damage. Microglia were activated in affected areas but without significant influx of B-cells, T-helper cells, or T-cytotoxic cells. Analysis of the model on a RAG-1 (recombination activating gene-1)-deficient background, lacking functional lymphocytes, did not change the observed disease and pathology compared with immunecompetent mice. We conclude that this model provides the opportunity to study the consequences of adult oligodendrocyte death in the absence of primary axonal injury and reactive cells of the adaptive immune system. Our results indicate that if the blood-brain barrier is not disrupted, myelin debris is not removed efficiently, remyelination is impaired, and axonal integrity is compromised, likely as the result of myelin detachment. This model will allow the evaluation of strategies aimed at improving remyelination to foster axon protection.

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…For example, oligodendrocyte-specific deletions in myelin associated genes PLP, MAG, and CNPase do not cause any obvious defect in myelination, but eventually lead to axonal pathology [12][13][14]. Moreover, axon degeneration has recently been observed as a consequence of geneticallyinduced oligodendrocyte-specific ablation [15], thus providing compelling evidence that axon survival is dependent on intact oligodendrocytes, and that axon degeneration in chronically demyelinated lesions can occur independently of inflammation. The presence of low-grade inflammation (mainly cells of the innate immune response) has led to the suggestion that this inflammatory response may also contribute to progressive attritional axonal loss.…”

Molecular triggers of neuroinflammation in mouse models of demyelinating diseases

“…Alternatively, there are underlying signals from degenerating neurons and axons that cause T cell infiltration, which are therefore due to secondary axonal loss in myelin mutant mice. Among different models, the variability of axonal involvement differs and perturbations of myelin function (in Plp1 trangenic mice) may be more detrimental to axon survival than transient demyelination induced by diphtheria toxin (Locatelli et al, 2012;Pohl et al, 2011;Traka et al, 2010). We note that, in contrast to oligodendrocytes, the genetic ablation of adult hippocampal neurons in transgenic mice with an inducible diphteria toxin gene causes significant infiltration of T cells (Agarwal et al, 2012 …”

“…Similarly, cross-breeding Plp1 transgenics with β2m KO mice (in which the lack of β2-microglobulin prevents the assembly of functional MHC class I) could help decide whether it is MHC class I-dependant mechanisms of infiltrating CD8 + cells (Linker et al, 2005) that contribute to demyelination and axonopathy in this model. Surprisingly, massive killing of transgenic oligodendrocytes with diphtheria toxin causes widespread demyelination and microglia/macrophage activation, but is not sufficient to attract a significant number of T cells (Locatelli et al, 2012;Pohl et al, 2011;Traka et al, 2010).…”

Remyelination Therapy for Multiple Sclerosis

“…Emerging models of demyelination are taking advantage of conditional cell ablation technology to specifically target oligodendrocytes. In these models, axonal pathology follows secondary to primary oligodendrocyte death [2,14]. Interestingly, one of these studies reports axonal damage and loss of 26 % of oligodendrocyte cell bodies, despite no widespread demyelination, further aiding support to the suggestion that oligodendrocytes confer more properties to underlying axons than just insulation [14].…”

“…It is believed that chronic demyelination of CNS axons leads to further axonal injury and neuronal death, and has been postulated to underlie this progression [1]. Indeed, experimental models of toxic myelin damage or myelin-interfering gene mutations result in subsequent axonal injury [2,3]. An emerging focus in MS treatment is the development of strategies to restore lost myelin.…”