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The Journal of Neuroscience, April 6, 2005, 25(14):3539-3550; doi:10.1523/JNEUROSCI.0081-05.2005

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

Mark S. Forman,^1,2 Devika Lal,¹ Bin Zhang,¹ Deepa V. Dabir,¹ Eric Swanson,¹ Virginia M.-Y. Lee,^1,2 and John Q. Trojanowski^1,2

¹Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and ²Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

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.

Key words: tau protein; astrocytes; neurodegeneration; tauopathy; transgenic mice; blood- brain barrier

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Received Jan 7, 2005; revised February 25, 2005; accepted February 27, 2005.

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