Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein

Mutations in the human tau gene cause frontotemporal dementia and parkinson ism linked to chromosome 17, Some mutations, including mutations in intron 10, induce increased levels of the functionally normal four-repeat tau prot ein isoform, leading to neurodegeneration, We generated transgenic mice tha t overexpress the four-repeat human tau protein isoform specifically in neu rons. 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 accompan ying dysfunctional sensorimotor capacities were transgene-dosage related. T hese findings proved that merely increasing the concentration of the four-r epeat tau protein isoform is sufficient to injure neurons in the central ne rvous system, without formation of intraneuronal neurofibrillary tangles. E vidence 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 feat ures of known neurodegenerative diseases, including Alzheimer's disease and other tauopathies. The model makes it possible to study the interaction wi th additional factors, to be incorporated genetically, or with other biolog ical triggers that are implicated in neurodegeneration.