title: Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein.
abstract: 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.
authors.affiliation: Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, Katholieke Universiteit Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Spittaels
authors.forename: C
authors.initials: C
authors.lastname: Van den Haute
authors.forename: J
authors.initials: J
authors.lastname: Van Dorpe
authors.forename: K
authors.initials: K
authors.lastname: Bruynseels
authors.forename: K
authors.initials: K
authors.lastname: Vandezande
authors.forename: I
authors.initials: I
authors.lastname: Laenen
authors.forename: H
authors.initials: H
authors.lastname: Geerts
authors.forename: M
authors.initials: M
authors.lastname: Mercken
authors.forename: R
authors.initials: R
authors.lastname: Sciot
authors.forename: A
authors.initials: A
authors.lastname: Van Lommel
authors.forename: R
authors.initials: R
authors.lastname: Loos
authors.forename: F
authors.initials: F
authors.lastname: Van Leuven
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D020033:Protein Isoforms; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins