Abstract
The mechanisms underlying oligodendrocyte (OLG) loss and the precise roles played by OLG death in human demyelinating diseases such as multiple sclerosis (MS), and in the rodent model of MS, experimental autoimmune encephalomyelitis (EAE), remain to be elucidated. To clarify the involvement of OLG death in EAE, we have generated transgenic mice that express the baculovirus anti-apoptotic protein p35 in OLGs through the Cre-loxP system. OLGs from cre/p35 transgenic mice were resistant to tumor necrosis factor-alpha-, anti-Fas antibody- and interferon-gamma-induced cell death. cre/p35 transgenic mice were resistant to EAE induction by immunization with the myelin oligodendrocyte glycoprotein. The numbers of infiltrating T cells and macrophages/microglia in the EAE lesions were significantly reduced, as were the numbers of apoptotic OLGs expressing the activated form of caspase-3. Thus, inhibition of apoptosis in OLGs by p35 expression alleviated the severity of the neurological manifestations observed in autoimmune demyelinating diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Caspase Inhibitors*
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Demyelinating Autoimmune Diseases, CNS / metabolism
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Demyelinating Autoimmune Diseases, CNS / prevention & control*
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Disease Models, Animal
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Enzyme Inhibitors / metabolism
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Gene Expression
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Gene Targeting*
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Immunohistochemistry
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Inhibitor of Apoptosis Proteins
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Interferon-gamma / pharmacology
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Mice
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Mice, Transgenic
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Myelin Proteins
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Myelin-Associated Glycoprotein / immunology
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Myelin-Oligodendrocyte Glycoprotein
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Oligodendroglia / metabolism*
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RNA, Messenger / metabolism
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Spinal Cord / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Viral Proteins / genetics*
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fas Receptor / pharmacology
Substances
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Caspase Inhibitors
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Enzyme Inhibitors
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Inhibitor of Apoptosis Proteins
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MOG protein, human
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Mog protein, mouse
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Myelin Proteins
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Myelin-Associated Glycoprotein
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Myelin-Oligodendrocyte Glycoprotein
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RNA, Messenger
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Tumor Necrosis Factor-alpha
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Viral Proteins
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fas Receptor
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inhibitor of apoptosis, Nucleopolyhedrovirus
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Interferon-gamma