Transgenic Mouse Model of Tau Pathology in Astrocytes Leading to Nervous System Degeneration

Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of sporadic and familial tauopathies. Because tau gene mutations are pathogenic for the autosomal dominant tauopathy "frontotemporal dementia and parkinsonism linked to chromosome 17," tau abnormalities are impl...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of neuroscience 2005-04, Vol.25 (14), p.3539-3550
Main Authors: Forman, Mark S, Lal, Devika, Zhang, Bin, Dabir, Deepa V, Swanson, Eric, Lee, Virginia M.-Y, Trojanowski, John Q
Format: Article
Language:English
Subjects:
Age Factors
Animals
Astrocytes - metabolism
Astrocytes - pathology
Axons - metabolism
Axons - pathology
Axons - ultrastructure
Blood-Brain Barrier - pathology
Blotting, Western - methods
Brain - metabolism
Brain - pathology
Disease Models, Animal
Gene Expression - physiology
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Humans
Immunohistochemistry - methods
Mice
Mice, Transgenic
Microscopy, Immunoelectron - methods
Nerve Degeneration - genetics
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
Neurobiology of Disease
Neurofibrillary Tangles - metabolism
Neurofibrillary Tangles - ultrastructure
Neurofilament Proteins - metabolism
tau Proteins - genetics
tau Proteins - metabolism
Ubiquitin - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of sporadic and familial tauopathies. Because tau gene 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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0081-05.2005