Accelerated development of neurochemical and behavioral deficits in LP-BM5 infected mice with targeted deletions of the IFN-gamma gene.
Mice homozygous for a germline deletion of the interferon-gamma gene (IFN-gamma (-/-)) were infected with the LP-BM5 (BM5) retrovirus mixture to determine if the inability to produce IFN-gamma reduces collateral CNS damage associated with chronic neuroinflammation. Virus burdens in spleens and brains of infected mice were comparable, but spatial memory deficits were manifested earlier and to a greater extent in BM5/IFN-gamma (-/-) mice. The mice with spatial memory deficits showed considerable degradation of axons and microtubules, along with apoptosis of striatal neurons. These lesions were accompanied by extensive infiltration of perivascular spaces and ventricles by iNOS-positive leukocytes, and a 17-fold increase in CSF glutamate levels. Despite high levels of VCAM and ICAM expression on cerebral vasculature endothelia, the serum levels of soluble ICAM-1 were significantly decreased in BM5/IFN-gamma (-/-) mice, which may contribute to the enhanced leukocyte infiltration and subsequent neuronal damage. These results suggest that the presence of IFN-gamma is necessary at some points in the inflammatory process to protect against neurodegeneration.
Koustova
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Laboratory of Bioorganic Chemistry, Building 8, Room 1A15, MSC 0826, NIDDK, NIH, Bethesda, MD 20892, USA.
Sei
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McCarty
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Espey
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Ming
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Morse
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Basile
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D000818:Animals; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D002634:Chemotaxis, Leukocyte; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D018698:Glutamic Acid / Q000134:cerebrospinal fluid; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007962:Leukocytes / Q000201:enzymology / Q000276:immunology; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology* / Q000821:virology*; D009474:Neurons / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D012190:Retroviridae / Q000502:physiology*; D013028:Space Perception / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000821:virology; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood / Q000378:metabolism; D019562:Viral Load
D008869:Microtubule-Associated Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D018698:Glutamic Acid; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse