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The Journal of Neuroscience, October 12, 2005, 25(41):9434-9443; doi:10.1523/JNEUROSCI.2691-05.2005

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Neurobiology of Disease
Axonal Degeneration Induced by Targeted Expression of Mutant Human Tau in Oligodendrocytes of Transgenic Mice That Model Glial Tauopathies

Makoto Higuchi, Bin Zhang, Mark S. Forman, Yasumasa Yoshiyama, John Q. Trojanowski, and Virginia M.-Y. Lee

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

Abundant filamentous tau inclusions in oligodendrocytes (OLGs) are hallmarks of neurodegenerative tauopathies, including sporadic corticobasal degeneration and hereditary frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, mechanisms of neurodegeneration in these tauopathies are unclear in part because of the lack of animal models for experimental analysis. We address this by generating transgenic (Tg) mice expressing human tau exclusively in OLGs using the 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter. Filamentous OLG tau inclusions developed in these Tg mice as a result of human tau expression in OLGs, especially those expressing the FTDP-17 human P301L mutant tau. Notably, structural disruption of myelin and axons preceded the emergence of thioflavin-S positive tau inclusions in OLGs, but impairments in axonal transport occurred even earlier, whereas motor deficits developed subsequently, especially in Tg mice with the highest tau expression levels. These data suggest that the accumulation of tau in OLG cause neurodegeneration, and we infer they do so by disrupting axonal transport. We suggest that similar defects may also occur in sporadic and hereditary human tauopathies with OLG tau pathologies.

Key words: tau; transgenic mouse; oligodendrocyte; myelin; neurodegeneration; axonal transport

Received June 29, 2005; revised September 2, 2005; accepted September 3, 2005.




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Overexpression of Wild-Type Murine Tau Results in Progressive Tauopathy and Neurodegeneration
Am. J. Pathol., October 1, 2009; 175(4): 1598 - 1609.
[Abstract] [Full Text] [PDF]


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