Abnormal Iron Deposition Associated With Lipid Peroxidation in Transgenic Mice Expressing Interleukin-6 in the Brain
| Autor: | Iain L. Campbell, Joseph L. Witztum, Henry C. Powell, Wulf Palinski, Robert S. Garrett, Pierre Castelnau |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Genetically modified mouse medicine.medical_specialty Pathology Iron Central nervous system Mice Transgenic Transferrin receptor Biology Blood–brain barrier Pathology and Forensic Medicine Lipofuscin Mice Cellular and Molecular Neuroscience Iron-Binding Proteins Internal medicine Glial Fibrillary Acidic Protein Receptors Transferrin medicine Animals chemistry.chemical_classification Interleukin-6 Spectrophotometry Atomic Neurodegeneration Transferrin Brain Iron-binding proteins General Medicine Transferrin-Binding Proteins medicine.disease Immunohistochemistry Mice Inbred C57BL Endocrinology medicine.anatomical_structure nervous system Neurology chemistry Blood-Brain Barrier Ferritins Female Lipid Peroxidation Neurology (clinical) Carrier Proteins |
| Zdroj: | Journal of Neuropathology & Experimental Neurology. 57:268-282 |
| ISSN: | 1554-6578 0022-3069 |
| DOI: | 10.1097/00005072-199803000-00008 |
| Popis: | Transgenic mice, named GFAP-IL6, that express interleukin-6 in astrocytes in the central nervous system (CNS) have a constitutive blood-brain barrier (BBB) defect and develop a progressive neurodegenerative disease. Based on ultrastructural observations showing electron-dense pigment in the brain of the GFAP-IL6 mice, we hypothesized that iron metabolism was altered in the brains of these animals. Enhanced histochemical methods revealed abnormal iron deposition in the cerebellum from 1 month of age that worsened with progression of the disease. Immunohistochemical analysis of iron-binding proteins (IBP) showed increased ferritin immunoreactivity and a decreased signal from the transferrin receptor in symptomatic animals. Atomic absorption spectroscopy revealed a 40% increase of total iron concentration in the cerebellum at the symptomatic stage. In order to obtain evidence that accumulation of this oxidizing metal was toxic, we looked for the presence of oxidative damage. Using the MAL-2 antibody, extensive lipid peroxidation (LP) was detected in the neocortex and the cerebellum in symptomatic animals. Ultrastructural analysis indicated lipofuscin deposition at the sites of neuro-axonal degeneration and abnormal iron deposition. These results suggest that the IL6-induced BBB defect precipitates iron accumulation in the GFAP-IL6 mouse brain and that subsequent IBP regulation mediates protective responses. As these defenses become overwhelmed, the iron overload seems to promote LP, which may contribute to the neurodegeneration that ensues. This transgenic mouse model of IL6-mediated neurodegeneration provides a unique opportunity to examine several aspects of iron metabolism in the brain, including its entry at the site of the BBB, its distribution through the IBP, and its mechanisms of toxicity. |
| Databáze: | OpenAIRE |
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