Transgenic Mouse Model of Tau Pathology in Astrocytes Leading to Nervous System Degeneration
| Autor: | Deepa Dabir, Eric Swanson, Mark S. Forman, John Q. Trojanowski, Devika Lal, Bin Zhang, Virginia M.-Y. Lee |
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| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Genetically modified mouse
Pathology medicine.medical_specialty Tau protein Blotting Western Green Fluorescent Proteins Gene Expression Mice Transgenic tau Proteins Biology Gene mutation Frontotemporal dementia and parkinsonism linked to chromosome 17 Mice Neurofilament Proteins Neurobiology of Disease mental disorders medicine Animals Humans Microscopy Immunoelectron Glial fibrillary acidic protein Ubiquitin General Neuroscience Neurodegeneration Age Factors Brain Neurofibrillary Tangles medicine.disease Immunohistochemistry Axons Disease Models Animal medicine.anatomical_structure nervous system Blood-Brain Barrier Astrocytes Nerve Degeneration biology.protein Neuron Tauopathy |
| Popis: | Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of sporadic and familial tauopathies. Becausetaugene mutations are pathogenic for the autosomal dominant tauopathy “frontotemporal dementia and parkinsonism linked to chromosome 17,” tau abnormalities are implicated directly in the onset and/or progression of disease. Although filamentous tau aggregates are acknowledged to play roles in degenerative mechanisms resulting in neuron loss, the contributions of glial tau pathology to neurodegeneration remain essentially unexplored. To begin to elucidate the role of glial pathology in tauopathies, we generated a transgenic (Tg) mouse model of astrocytic tau pathology by expressing the human tau protein driven by the glial fibrillary acidic protein (GFAP) promoter. Whereas endogenous tau was not detected in astrocytes of control mice, in GFAP/tau Tg mice there was robust astrocytic tau expression that was associated with a redistribution of the GFAP network. Subsequently, there was an age-dependent accumulation of tau pathology in astrocytes that was Gallyas and variably thioflavine S positive as observed in many tauopathies. The tau pathology in these Tg mice was abnormally phosphorylated, ubiquitinated, and filamentous, and the emergence of this pathology coincided with accumulation of insoluble tau protein. Furthermore, in regions with robust astrocytic tau pathology, there was mild blood- brain barrier disruption, induction of low-molecular-weight heat shock proteins, and focal neuron degeneration. Thus, these Tg mice recapitulate key features of astrocytic pathology observed in human tauopathies and demonstrate functional consequences of this pathology including neuron degeneration in the absence of neuronal tau inclusions. |
| Databáze: | OpenAIRE |
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