Dataset Information

A comparative study of experimental mouse models of central nervous system demyelination.

ABSTRACT: Several mouse models of multiple sclerosis (MS) are now available. We have established a mouse model, in which ocular infection with a recombinant HSV-1 that expresses murine interleukin (IL)-2 constitutively (HSV-IL-2) causes central nervous system demyelination in different strains of mice. This model differs from most other models, in which it represents a mixture of viral and immune triggers. In the present study, we directly compared MOG35-55, MBP35-47 and PLP190-209 models of experimental autoimmune encephalitis with our HSV-IL-2-induced MS model. Mice with HSV-IL-2- and myelin oligodendrocyte glycoprotein (MOG)-induced demyelinating diseases demonstrated a similar pattern and distribution of demyelination in their brain, spinal cord (SC) and optic nerves (ONs). In contrast, no demyelination was detected in the ONs of myelin basic protein (MBP)- and proteolipid protein (PLP)-injected mice. Interferon-? (IFN-?) injections significantly reduced demyelination in brains of all groups, in the SCs of the MOG and MBP groups, and completely blocked it in the SCs of the PLP and HSV-IL-2 groups as well as in ONs of MOG and HSV-IL-2 groups. In contrast to IFN-? treatment, IL-12p70 protected the HSV-IL-2 group from demyelination, whereas IL-4 was not effective at all in preventing demyelination. MOG-injected mice showed clinical signs of paralysis and disease-related mortality, whereas mice in the other treatment groups did not. Collectively, the results indicate that the HSV-IL-2 model and the MOG model complement each other and, together, provide unique insights into the heterogeneity of human MS.

SUBMITTER: Dumitrascu OM

PROVIDER: S-EPMC4047154 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A comparative study of experimental mouse models of central nervous system demyelination.

Dumitrascu O M OM Mott K R KR Ghiasi H H

Gene therapy 20140410 6

Several mouse models of multiple sclerosis (MS) are now available. We have established a mouse model, in which ocular infection with a recombinant HSV-1 that expresses murine interleukin (IL)-2 constitutively (HSV-IL-2) causes central nervous system demyelination in different strains of mice. This model differs from most other models, in which it represents a mixture of viral and immune triggers. In the present study, we directly compared MOG35-55, MBP35-47 and PLP190-209 models of experimental ...[more]

PMID: 24718267

Similar Datasets

Project description:IntroductionChronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients.MethodsBrain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms.ResultsAnalyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or "zebra bodies" consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice.DiscussionOur findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.

Project description:Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized, and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss. To unambiguously identify the effects of oligodendrocyte death in the absence of inflammatory stimulation, we developed a method for experimentally inducing programmed cell death selectively in mature oligodendrocytes and assessed the effects on demyelination, immunological stimulation, and gliosis. The resulting pathology is discussed relative to observed MS pathologies.Oligodendrocyte apoptosis was induced in the adult rat brain using a lentivirus to express experimentally inducible caspase 9 (iCP9) cDNA under transcriptional control of the promoter for myelin basic protein, which is oligodendrocyte-specific. Activation of iCP9 was achieved by distal injection of a small molecule dimerizer into the lateral ventricle resulting in localized, acute oligodendrocyte apoptosis.Induced oligodendrocyte apoptosis resulted in rapid demyelination and robust, localized microglial activation in the absence of peripheral immune cell infiltration. Lesion borders showed layers of preserved and degraded myelin, whereas lesion cores were demyelinated but only partially cleared of myelin debris. This resulted in local proliferation and mobilization of the oligodendrocyte progenitor pool.This approach provides a novel model to understand the pathological changes that follow from localized apoptosis of myelinating oligodendrocytes. It provides the first direct proof that initiation of apoptosis in oligodendrocytes is sufficient to cause rapid demyelination, gliosis, and a microglial response that result in lesions sharing some pathological characteristics with a subset of MS lesions.

Dataset Information

A comparative study of experimental mouse models of central nervous system demyelination.

Publications

A comparative study of experimental mouse models of central nervous system demyelination.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets