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Animal Models |
From the Experimental Genetics Group,*
Center for Human
Genetics, Flemish Institute for Biotechnology, Katholieke Universiteit
Leuven, Leuven; the Janssen Research
Foundation,
Beerse; the Department of
Pathology,
University Hospitals Leuven,
Leuven; and the Department of Genetic
Epidemiology,§
Katholieke Universiteit Leuven,
Leuven, Belgium
Mutations in the human tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Some mutations, including mutations in intron 10, induce increased levels of the functionally normal four-repeat tau protein isoform, leading to neurodegeneration. We generated transgenic mice that overexpress the four-repeat human tau protein isoform specifically in neurons. The transgenic mice developed axonal degeneration in brain and spinal cord. In the model, axonal dilations with accumulation of neurofilaments, mitochondria, and vesicles were documented. The axonopathy and the accompanying dysfunctional sensorimotor capacities were transgene-dosage related. These findings proved that merely increasing the concentration of the four-repeat tau protein isoform is sufficient to injure neurons in the central nervous system, without formation of intraneuronal neurofibrillary tangles. Evidence for astrogliosis and ubiquitination of accumulated proteins in the dilated part of the axon supported this conclusion. This transgenic model, overexpressing the longest isoform of human tau protein, recapitulates features of known neurodegenerative diseases, including Alzheimer’s disease and other tauopathies. The model makes it possible to study the interaction with additional factors, to be incorporated genetically, or with other biological triggers that are implicated in neurodegeneration.
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P. Heutink Untangling tau-related dementia Hum. Mol. Genet., April 1, 2000; 9(6): 979 - 986. [Abstract] [Full Text] [PDF]
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I. Tesseur, J. Van Dorpe, K. Spittaels, C. Van den Haute, D. Moechars, and F. Van Leuven Expression of Human Apolipoprotein E4 in Neurons Causes Hyperphosphorylation of Protein Tau in the Brains of Transgenic Mice Am. J. Pathol., March 1, 2000; 156(3): 951 - 964. [Abstract] [Full Text] [PDF]
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K. Spittaels, C. Van den Haute, J. Van Dorpe, H. Geerts, M. Mercken, K. Bruynseels, R. Lasrado, K. Vandezande, I. Laenen, T. Boon, et al. Glycogen Synthase Kinase-3beta Phosphorylates Protein Tau and Rescues the Axonopathy in the Central Nervous System of Human Four-repeat Tau Transgenic Mice J. Biol. Chem., December 22, 2000; 275(52): 41340 - 41349. [Abstract] [Full Text] [PDF]
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J. Gotz, F. Chen, R. Barmettler, and R. M. Nitsch Tau Filament Formation in Transgenic Mice Expressing P301L Tau J. Biol. Chem., January 5, 2001; 276(1): 529 - 534. [Abstract] [Full Text] [PDF]
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