The response of NG2-expressing oligodendrocyte progenitors to demyelination in MOG-EAE and MS

Remyelination of primary demyelinated lesions is a common feature of experimental models of multiple sclerosis (MS) and is also suggested to be the normal response to demyelination during the early stages of MS itself. Many lines of evidence have shown that remyelination is preceded by the division of endogenous oligodendrocyte precursor cells (OPCs) in the lesion and its borders. It is suggested that this rapid response of OPCs to repopulate the lesion site and their subsequent differentiation into new oligodendrocytes is the key to the rapid remyelination. Antibodies to the NG2 chondroitin sulphate proteoglycan have proved exceedingly useful in following and quantitating the response of endogenous OPCs to demyelination. Here we review the literature on the response of NG2-expressing OPCs to demyelination and provide some new evidence on their response to the chronic inflammatory demyelinating environment seen in recombinant myelin oligodendrocyte glycoprotein (MOG) induced experimental allergic encephalomyelitis (EAE) in the DA rat. NG2-expressing OPCs responded to the inflammatory demyelination in this model by becoming reactive and increasing in number in a very focal manner. Evidence of NG2⁺OPCs in lesioned areas beginning to express the oligodendrocyte marker CNP was also seen. The response of OPCs appeared to occur following successive relapses but did not always lead to remyelination, with areas of chronic demyelination observed in the spinal cord. The presence of OPCs in the adult human CNS is clearly of vital importance for repair in multiple sclerosis (MS). As in rat tissue, the antibody labels an evenly distributed cell population present in both white and grey matter, distinct from HLA-DR⁺microglia. NG2⁺cells are sparsely distributed in the centre of chronic MS lesions. These cells apparently survive demyelination and exhibit a multi-processed or bipolar morphology in the very hypocellular environment of the lesion.     

Demyelination and remyelination in the rat central nervous system following ethidium bromide injection

Intracisternal injection of ethidium bromide induced status spongiosus with prominent degenerative changes in oligodendroglia in the subpial regions of the central nervous system of the rat. Chronologic investigation of the lesions has revealed that status spongiosus resulted in myelin degeneration, and by the 6th day postinjection many axons were demyelinated. At this time, numerous debris-filled phagocytic cells were observed among the totally naked axons. Vesicular transformation of myelin was the common degenerative change. Features suggestive of separation of myelin lamellae by phagocytic cells were also observed. In the demyelinated areas, oligodendroglial cells disappeared completely. By the 12th day postinjection, remyelination was apparent and numerous active oligodendroglia appeared in association with thinly myelinated axons. Some central nervous system axons were myelinated by Schwann cells. These patterns of demyelination and remyelination observed in ethidium bromide-treated rats were compared with those observed in other demyelinating conditions of varied etiology such as experimental allergic encephalomyelitis, diphtheria toxin, or lysolecithin injection and cuprizone intoxication.     

Failure of remyelination in the nonhuman primate optic nerve

The mechanisms limiting myelin repair in human central nervous system (CNS) remain unknown. Models of induced-demyelination in the nonhuman primate CNS may provide the necessary grounds to unravel these mechanisms and to investigate the development of strategies to promote myelin repair. To address this issue, we developed a model of focal demyelination in the adult Macaca fascicularis CNS. Lesions were induced by microinjection of lysolecithin in the optic nerve and the profile of remyelination was compared to that of lysolecithin-induced lesions of the spinal cord. In both structures, the time-course of demyelination as well as the onset of remyelination were found to be similar to that in the rodent CNS. While spinal cord lesions were remyelinated within 6 weeks, optic nerve lesions remained demyelinated for up to 3 months post-injection.The failure of remyelination in the optic nerve correlated with a reduced density of NG2+ oligodendrocyte progenitor cells, the presence of oligodendrocytes that fail to ensheath naked axons in the lesion and the absence of astrocyte recruitment in the lesion compared with spinal cord lesions. Our present data suggest that the reduced oligodendrocyte progenitor population, the improper activation of oligodendrocytes at the onset of remyelination in the optic nerve, and possibly, the involvement of astrocytes contribute to the chronicity of the optic nerve lesion. This model of chronic demyelination in the macaque optic nerve stresses its pertinence to unraveling the mechanisms limiting remyelination in multiple sclerosis.     

The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system

Myelin of the adult CNS is vulnerable to a variety of metabolic, toxic, and autoimmune insults. That remyelination can ensue, following demyelinating insult, has been well demonstrated. Details of the process of remyelination are, however difficult to ascertain since in most experimental models of demyelination/remyelination the severity, localization of lesion site, or time course of the pathophysiology is variable from animal to animal. In contrast, an experimental model in which massive demyelination can be reproducibly induced in large areas of mouse brain is exposure to the copper chelator, cuprizone, in the diet. We review work from several laboratories over the past 3 decades, with emphasis on our own recent studies, which suggest an overall picture of cellular events involved in demyelination/remyelination. When 8 week old C57BL/6 mice are fed 0.2% cuprizone in the diet, mature olidgodendroglia are specifically insulted (cannot fulfill the metabolic demand of support of vast amounts of myelin) and go through apoptosis. This is closely followed by recruitment of microglia and phagoctytosis of myelin. Studies of myelin gene expression, coordinated with morphological studies, indicate that even in the face of continued metabolic challenge, oligodendroglial progenitor cells proliferate and invade demyelinated areas. If the cuprizone challenge is terminated, an almost complete remyelination takes place in a matter of weeks. Communication between different cell types by soluble factors may be inferred. This material is presented in the context of a model compatible with present data -- and which can be tested more rigorously with the cuprizone model. The reproducibility of the model indicates that it may allow for testing of manipulations (e.g. available knockouts or transgenics on the common genetic background, or pharmacological treatments) which may accelerate or repress the process of demyelination and or remyelination.     

Deleterious role of IFNgamma in a toxic model of central nervous system demyelination

Interferon-gamma (IFNgamma) is a pleiotropic cytokine that plays an important role in many inflammatory processes, including autoimmune diseases such as multiple sclerosis (MS). Demyelination is a hallmark of MS and a prominent pathological feature of several other inflammatory diseases of the central nervous system, including experimental autoimmune encephalomyelitis, an animal model of MS. Accordingly, in this study we followed the effect of IFNgamma in the demyelination and remyelination process by using an experimental autoimmune encephalomyelitis model of demyelination/remyelination after exposure of mice to the neurotoxic agent cuprizone. We show that demyelination in response to cuprizone is delayed in mice lacking the binding chain of IFNgamma receptor. In addition, IFNgammaR(-/-) mice exhibited an accelerated remyelination process after cuprizone was removed from the diet. Our results also indicate that the levels of IFNgamma were able to modulate the microglia/macrophage recruitment to the demyelinating areas. Moreover, the accelerated regenerative response showed by the IFNgammaR(-/-) mice was associated with a more efficient recruitment of oligodendrocyte precursor cells in the demyelinated areas. In conclusion, this study suggests that IFNgamma regulates the development and resolution of the demyelinating syndrome and may be associated with toxic effects on both mature oligodendrocytes and oligodendrocyte precursor cells.     

Complete blood count and acetylcholinesterase activity of lymphocytes of demyelinated and ovariectomized rats treated with resveratrol

Resveratrol is a phytoestrogen that has many beneficial actions. This study aimed to evaluate the effect of resveratrol on the complete blood count (CBC) and the acetylcholinesterase (AChE) activity of lymphocytes of ovariectomized rats experimentally demyelinated by ethidium bromide (EB). Forty adult female Wistar rats (60 days, 200–220 g) were divided randomly into five groups (n = 4) to evaluate the demyelination phase and five groups (n = 4) to evaluate the remyelination phase. In each phase, the groups consisted of sham rats–G1; ovariectomized rats, not demyelinated, treated only with vehicle (ethanol 25%)–G2; demyelinated ovariectomized rats treated only with vehicle–G3; ovariectomized rats, not demyelinated, treated with resveratrol–G4; and demyelinated ovariectomized rats treated with resveratrol–G5. Only during the remyelination phase, CBC showed a significant difference (p < 0.05) in the number of monocytes between G2 and G5 groups. In the demyelination phase, there was a significant decrease (p < 0.05) in the AChE activity in the G4 group, while the G5 group was statistically similar to the G1, G2 and G4 groups. In the remyelination phase, there were no significant differences in the AChE activity among the groups. The treatment for 7 days with resveratrol with or without the experimental demyelization with EB appears to influence the AChE activity of lymphocytes, without changing the number of these cells in the circulation. However, in the remyelination phase, there seems to be stabilization in its effect on the lymphocyte AChE activity.     

AN2, the mouse homologue of NG2, is a surface antigen on glial precursor cells implicated in control of cell migration

Molecular studies have demonstrated that the murine AN2 antigen is the mouse homologue of the rat NG2 and human MCSP protein. The molecule is a single-pass transmembrane protein which carries a variable number of glyco- and glycosaminoglycan chains according to cell type and developmental stage. AN2/NG2 has two extracellular Laminin G-like domains which are classically involved in cell adhesion and recognition. It possesses a single PDZ binding motif in the short intracellular tail. The AN2/NG2 antigen is expressed by glial progenitor cells in developing and adult CNS and also by immature Schwann cells. Antibodies against AN2/NG2 inhibit the migration of antigen-positive cells in in vitroassays, suggesting that the molecule plays a role in migration. Many AN2/NG2-positive cells surround synapses in the developing and adult brain. A recently identified intracellular partner of AN2/NG2 is the glutamate receptor interacting protein GRIP, which binds to the GluRB subunit of the AMPA subclass of glutamate receptors. The AN2/NG2 protein may position AMPA receptors on perisynaptic glial cells towards active synapses by binding to a neuronal receptor. Many highly migratory neural tumors including melanomas express AN2/NG2. In the demyelinating disease Multiple Sclerosis, some patients synthesise antibodies against the protein. Such antibodies may play a pathological role by inhibiting the migration of oligodendrocyte progenitor cells to demyelinated axons thus blocking remyelination, as well as possibly interfering with glial neuronal signalling at synapses and nodes of Ranvier.     

Viral induced demyelination

Viral induced demyelination, in both humans and rodent models, has provided unique insights into the cell biology of oligodendroglia, their complex cell-cell interactions and mechanisms of myelin destruction. They illustrate mechanisms of viral persistence, including latent infections in which no infectious virus is readily evident, virus reactivation and viral-induced tissue damage.These studies have also provided excellent paradigms to study the interactions between the immune system and the central nervous system (CNS). Although of interest in their own right, an understanding of the diverse mechanisms used by viruses to induce demyelination may shed light into the etiology and pathogenesis of the common demyelinating disorder multiple sclerosis (MS). This notion is supported by the persistent view that a viral infection acquired during adolescence might initiate MS after a long period of quiescence. Demyelination in both humans and rodents can be initiated by infection with a diverse group of enveloped and non-enveloped RNA and DNA viruses (Table 1). The mechanisms that ultimately result in the loss of CNS myelin appear to be equally diverse as the etiological agents capable of causing diseases which result in demyelination. Although demyelination can be a secondary result of axonal loss, in many examples of viral induced demyelination, myelin loss is primary and associated with axonal sparing. This suggests that demyelination induced by viral infections can result from: 1) a direct viral infection of oligodendroglia resulting in cell death with degeneration of myelin and its subsequent removal; 2) a persistent viral infection, in the presence or absence of infectious virus, resulting in the loss of normal cellular homeostasis and subsequent oligodendroglial death; 3) a vigorous virus-specific inflammatory response wherein the virus replicates in a cell type other than oligodendroglia, but cytokines and other immune mediators directly damage the oligodendroglia or the myelin sheath; or 4) infection initiates activation of an immune response specific for either oligodendroglia or myelin components. Virus-induced inflammation may be associated with the processing of myelin or oligodendroglial components and their presentation to the host's own T cell compartment. Alternatively, antigenic epitopes derived from the viral proteins may exhibit sufficient homology to host components that the immune response to the virus activates autoreactive T cells, i.e. molecular mimicry. Although it is not clear that each of these potential mechanisms participates in the pathogenesis of human demyelinating disease, analysis of the diverse demyelinating viral infections of both humans and rodents provides examples of many of these potential mechanisms.     

Clusters of axonal Na+ channels adjacent to remyelinating Schwann cells

Summary Rat sciatic nerve fibres were demyelinated by injection of lysolecithin and examined at several stages as Schwann cells proliferated, adhered, and initiated remyelination. Immunoperoxidase EM has been used to follow the clustering of Na⁺ channels that represents an early step in the formation of new nodes of Ranvier. At the peak of demyelination, 1 week postinjection, only isolated sites, suggestive of the original nodes, were labelled. As Schwann cells adhered and extended processes along the axons, regions of axonal Na⁺ channel immunoreactivity were often found just beyond their leading edges. These channel aggregates were associated only with the axolemma and Na⁺ channels were not detected on glial membranes. Sites with more than one cluster in close proximity and broadly labelled aggregates between Schwann cells suggested that new nodes of Ranvier formed as neighbouring Na⁺ channel groups merged. Schwann cells thus seem to play a major role in ion channel distributions in the axolemma. In all of these stages Na⁺ channel label was found primarily just outside the region of close contact between axon and Schwann cell. This suggests that Schwann cell adherence acts in part to exclude Na⁺ channels, or that diffusible substances are involved and can act some distance from regions of direct contact.     

Antibody-mediated demyelination in experimental allergic encephalomyelitis is independent of complement membrane attack complex formation.

The effects of decomplementation by cobra venom factor (CVF) on the pathogenesis of inflammation and demyelination in experimental allergic encephalomyelitis (EAE) and acute antibody-mediated demyelinating EAE (ADEAE) have been quantified histologically and immunocytochemically. In rats immunized with 50 micrograms of myelin basic protein in Freund's complete adjuvant containing 100 micrograms heat-killed Mycobacterium tuberculosis H37Ra, clinical signs of EAE were completely suppressed by two injections of CVF given 9 and 12 days post-immunization. Suppression of clinical disease was associated with a dramatic reduction in peri-vascular inflammation in the CNS, although immunohistochemical staining identified small numbers of infiltrating T cells and macrophages. In contrast, CVF treatment had no significant effect on the clinical severity of ADEAE and although C9 deposition within the CNS was virtually abolished, there was no statistically significant decrease in the extent of demyelination or inflammation. These observations indicate that in the absence of complement components C3 and C5 an antibody-dependent cell-mediated cytotoxic response plays an important role in the pathogenesis of antibody-mediated demyelination. The major role of the complement cascade in EAE appears to be the generation of pro-inflammatory factors that enhance the inflammatory response within the CNS in animals facing a mild encephalitogenic challenge.     

Oligodendrocyte‐specific deletion of FGFR2 ameliorates MOG35‐55‐induced EAE through ERK and Akt signalling

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte‐specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG_35‐55‐induced EAE. Oligodendrocyte‐specific knockout of FGFR2 (Fgfr2^{ind −/−}) was achieved by application of tamoxifen; EAE was induced using the MOG_35‐55 peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2^{ind −/−} mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2^{ind −/−} mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2^{ind −/−} mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2^{ind −/−} mice. Furthermore, expression of IL‐1β, TNF‐α and CD200 was less in Fgfr2^{ind −/−} mice than controls. Fgfr2^{ind −/−} mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF‐β expression. These data suggest that cell‐specific deletion of FGFR2 in oligodendrocytes has anti‐inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS.     

Ultrastructure of Multiple Sclerosis

The electron microscopic features of 11 stereotaxic brain biopsies that demonstrated inflammatory primary demyelination consistent both morphologically and clinically with multiple sclerosis are addressed. Degeneration of inner oligodendrog-lial loops and uniform widening of inner myelin lamellae antedated complete destruction of myelin sheaths. Perivascular lymphocytes, macrophages, and plasma cells were in intimate contact with myelin sheaths. Astrocytes proliferated even away from demyelinated areas. In areas of chronic, established demyelination, oligodendrocyte numbers were greatly decreased, and fields of completely demyelinated axons were seen among astrocytic processes. Axonal injury, evidenced by the formation of axonal swellings, was apparent in maximally affected areas. At the edge of acute lesions with demyelinated axons, oligodendrocytes were preserved morphologically. Thinly myelinated axons indicative of central nervous system-type remyelination by oligodendrocytes were observed primarily at the edges of plaques. An unusual inclusion observed in presumed macrophages was “polelike” bodies 0.04- to 0.7-(jim thick. Linearly arrayed, their presumably proteinaceous crystalline substance was moderately electron-dense. Many were membrane-bound and appeared to arise from the endoplasmic reticulum. We conclude that disturbance of the myelinating function of oligodendrocytes may be a critical event in the pathogenesis of multiple sclerosis.     

Microglial recruitment, activation, and proliferation in response to primary demyelination

We have characterized the cellular response to demyelination/remyelination in the central nervous system using the toxin cuprizone, which causes reproducible demyelination in the corpus callosum. Microglia were distinguished from macrophages by relative CD45 expression (CD45(dim)) using flow cytometry. Their expansion occurred rapidly and substantially outnumbered infiltrating macrophages and T cells throughout the course of cuprizone treatment. We used bromodeoxyuridine incorporation and bone marrow chimeras to show that both proliferation and immigration from blood accounted for increased microglial numbers. Microglia adopted an activated phenotype during demyelination, up-regulating major histocompatibility class I and B7.2/CD86. A subpopulation of CD45(dim-high) microglia that expressed reduced levels of CD11b emerged during demyelination. These microglia expressed CD11c and were potent antigen-presenting cells in vitro. T cells were recruited to the demyelinated corpus callosum but did not appear to be activated. Our study highlights the role of microglia as a heterogeneous population of cells in primary demyelination, with the capacity to present antigen, proliferate, and migrate into demyelinated areas.     

Schwann cell remyelination of CNS axons following injection of cultures of CNS cells into areas of persistent demyelination

The injection of suspensions of central nervous system (CNS) cells, prepared by standard methods from 4-day-old rat brain and maintained in vitro for 10 days, into areas of persistent demyelination in rat spinal cord resulted in extensive remyelination of axons by Schwann cells. As control lesions injected with medium showed no remyelination, the most likely explanation of this finding is that 'CNS cultures' contain a small population of Schwann cells which are stimulated to proliferate by the demyelinated axons.     

Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury

Oligodendroglial injury is a pathological hallmark of many human white matter diseases, including multiple sclerosis (MS) and periventricular leukomalacia (PVL). Critical regulatory mechanisms of oligodendroglia destruction, however, remain incompletely understood. Ceramide, a bioactive sphingolipid pivotal to sphingolipid metabolism pathways, regulates cell death in response to diverse stimuli and has been implicated in neurodegenerative disorders. We report here that ceramide accumulates in reactive astrocytes in active lesions of MS and PVL, as well as in animal models of demyelination. Serine palmitoyltransferase, the rate-limiting enzyme for ceramide de novo biosynthesis, was consistently upregulated in reactive astrocytes in the cuprizone mouse model of demyelination. Mass spectrometry confirmed the upregulation of specific ceramides during demyelination, and revealed a concomitant increase of sphingosine and a suppression of sphingosine-1-phosphate, a potent signaling molecule with key roles in cell survival and mitogenesis. Importantly, this altered sphingolipid metabolism during demyelination was restored upon active remyelination. In culture, ceramide acted synergistically with tumor necrosis factor, leading to apoptotic death of oligodendroglia in an astrocyte-dependent manner. Taken together, our findings implicate that disturbed sphingolipid pathways in reactive astrocytes may indirectly contribute to oligodendroglial injury in cerebral white matter disorders.     

Do central nervous system axons remyelinate?

In multiple sclerosis (MS), one of the most frequent demyelinating diseases in man, remyelination of demyelinating lesions exists but is often incomplete. Also reported in experimental models of demyelination, this phenomenom confirms the regenerating potential of the demyelinated central nervous system (CNS) and, in particular, the existence of an endogenous mechanism of oligodendrocyte renewal. Failure in efficient remyelination could result from exhaustion of the pool of remyelinating cells, loss of axons and absence of a permissive environment for remyelination. Identifying the nature and the origin of the cells capable of generating new oligodendrocytes for remyelination could contribute to strategies to activate these cells, and thereby enhance their potential for myelin repair. Within the adult CNS, several cell types are capable of generating new oligodendrocytes following myelin damage: post-mitotic oligodendrocytes frequently found at the lesion site, oligodendrocyte progenitors whose existence has been confirmed both in vitro and in vivo, and multipotent cells localized in the germinative areas of the brain and the spinal cord. Although restricted to particular sites of the CNS, these multipotent cells, which maintain the capacity to self-renew and to migrate throughout adulthood, could constitute a powerful source of remyelinating cells. The study of the mechanisms of proliferation, migration and differentiation of these cells in response to demyelination should allow the definition of new strategies to promote endogenous remyelination and develop therapeutic approaches for demyelinating diseases such as MS. This goal is an appealing alternative to the transplantation of myelin-forming cells and should efficiently complement strategies aimed at reducing neuronal loss and inflammation.     

PERK Activation Preserves the Viability and Function of Remyelinating Oligodendrocytes in Immune-Mediated Demyelinating Diseases

Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease in the central nervous system (CNS). Regeneration of oligodendrocytes and subsequent remyelination are necessary to restore neurological function in patients with MS. Although the remyelination process occurs in the CNS of patients with MS, this remyelination is generally considered to be insufficient.^1,2 Increasingly, the evidence suggests that endoplasmic reticulum (ER) stress, which is caused by the accumulation of unfolded or misfolded proteins in the ER, plays a role in inflammatory diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE).^3–5 Activation of pancreatic ER kinase (PERK) in response to ER stress promotes a stress-resistant state through the global attenuation of protein translation and the induction of numerous cytoprotective genes. PERK activation, however, also triggers an apoptotic program to eliminate ER-stressed cells.^6,7 Although PERK activation has been observed in oligodendrocytes in MS and EAE demyelinated lesions,^8–10 the role that PERK signaling plays in remyelinating oligodendrocytes during the remyelination process remains elusive.Recently, we generated PLP/Fv2E-PERK transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. By using the unique mouse model, we found that enhanced activation of PERK signaling specifically in mature oligodendrocytes protected the cells and myelin against inflammatory attack in EAE mice.¹¹ Mature oligodendrocytes in adult mice are only responsible for the slow replenishment of myelin components. In contrast, remyelinating oligodendrocytes must synthesize enormous amounts of membrane lipid and protein molecules to assemble myelin sheaths. The cells have extremely high metabolic rates.^4,12 This feature makes remyelinating oligodendrocytes in MS and EAE demyelinated lesions more vulnerable to inflammatory attack and ER stress than mature oligodendrocytes.^12,13 Our previous studies have shown that ER stress, induced by interferon-γ (IFN-γ), protects mature oligodendrocytes and myelin against inflammatory attack during the acute stage of EAE, but causes remyelinating oligodendrocyte apoptosis and remyelination failure at the recovery stage of EAE.^8,14 Thus, in this study, we sought to dissect the precise role of PERK signaling in remyelinating oligodendrocytes in immune-mediated demyelinating diseases exploiting PLP/Fv2E-PERK mice.The immune cytokine, IFN-γ, is thought to be a major contributing factor to poor remyelination in MS lesions.^1,13 Our previous studies have shown that the presence of IFN-γ in the CNS causes hypomyelination in young, developing mice, and remyelination failure in the cuprizone and EAE models.^14,15 In this study, we demonstrate that persistent activation of PERK signaling does not affect the viability or function of (re)myelinating oligodendrocytes under normal conditions. Moreover, we show that enhancing PERK activation specifically in (re)myelinating oligodendrocytes attenuates IFN-γ–induced hypomyelination in young, developing mice and IFN-γ–induced remyelination failure in the cuprizone model. More important, we find that enhancing PERK activation specifically in remyelinating oligodendrocytes promotes remyelination in the EAE model. Our findings may lead to the development of therapeutic interventions to improve remyelination in patients with MS.