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Experimental Genetics Group
Am J Pathol, 1999 Dec;155(6):2153-2165. Spittaels K1, Van den Haute C1, Van Dorpe J1, Bruynseels K1, Vandezande K1, Laenen I1, Geerts H2, Mercken M2, Sciot R3, Van Lommel A3, Loos R4, Van Leuven F1. 1Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium. 2Janssen Research Foundation, Beerse, Belgium. 3Department of Pathology, University Hospitals Leuven, Leuven, Belgium. 4Department 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.  FULL TEXT |
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