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. INTERPRETATION: 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.
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. INTERPRETATION: 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: Esther C W Breij; Bianca P Brink; Rob Veerhuis; Christa van den Berg; Rianka Vloet; Riqiang Yan; Christine D Dijkstra; Paul van der Valk; Lars Bö Journal: Ann Neurol Date: 2008-01 Impact factor: 10.422
Authors: Michael R Elliott; Faraaz B Chekeni; Paul C Trampont; Eduardo R Lazarowski; Alexandra Kadl; Scott F Walk; Daeho Park; Robin I Woodson; Marina Ostankovich; Poonam Sharma; Jeffrey J Lysiak; T Kendall Harden; Norbert Leitinger; Kodi S Ravichandran Journal: Nature Date: 2009-09-10 Impact factor: 49.962
Authors: Ponnada A Narayana; Yuxiang Zhou; Khader M Hasan; Sushmita Datta; Xiaojun Sun; Jerry S Wolinsky Journal: Mult Scler Date: 2013-07-08 Impact factor: 6.312
Authors: Hongling Zhu; Francesca Ornaghi; Sophie Belin; Maria I Givogri; Lawrence Wrabetz; Ernesto R Bongarzone Journal: J Neurosci Res Date: 2016-07-18 Impact factor: 4.164
Authors: Andrew V Caprariello; Courtney E Batt; Ingrid Zippe; Rita R Romito-DiGiacomo; Molly Karl; Robert H Miller Journal: J Neurosci Date: 2015-10-14 Impact factor: 6.167