title: Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve School of Medicine, Cleveland, OH, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Caprariello
authors.forename: Saisho
authors.initials: S
authors.lastname: Mangla
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Selkirk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005732:Gangliosides / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein; D005912:Gliotoxin / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019081:O Antigens / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000502:physiology*; D055503:Protein Multimerization / Q000187:drug effects; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection / Q000379:methods
chemical_list: D053477:Apoptotic Protease-Activating Factor 1; D051792:Basic Helix-Loop-Helix Proteins; D053453:Caspase 9; D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D005912:Gliotoxin; D049452:Green Fluorescent Proteins; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D019081:O Antigens; D000076104:Oligodendrocyte Transcription Factor 2; D016559:Tacrolimus; C506594:Apaf1 protein, rat; C522729:Olig2 protein, rat; C062875:ganglioside A2B5; C506435:Casp9 protein, rat