Mouse Models Of Tauopathies

During the past several years, mutations in the tau gene linked to a heterogeneous group of neurodegen-

erative disorders characterized by filamentous tau inclusions have been identified. These disorders, collectively termed tauopathies, include sporadic and familial frontotemporal dementia with parkinsonism linked to chromosome 17, progressive supranuclear palsy, and Pick's disease. In humans, six tau isoforms (three isoforms with three microtubule-binding repeats and three isoform with four microtubule-binding repeats) are generated by alternative splicing of the tau gene in adult brain. In rodents, there are three four-repeat isoforms. To model neurodegenerative tauo-pathy, investigators have developed transgenic mice expressing high levels of wild-type tau isoforms. Overexpression of either the shortest or the longest tau human isoform in the brain and spinal cord of transgenic mice using either the Thy1 or the prion protein promoter, respectively, resulted in an age-dependent phenotype characterized by insoluble, hy-perphosphorylated tau and intraneuronal inclusions composed of tau-immunoreactive filaments. These tau inclusions are found in large numbers in spinal motor neurons. These mice showed axon degeneration and decreased axonal transport. Not surprisingly, they revealed motor impairments. Although these studies showed that the overexpression of a single tau isoform can develop filamentous tau inclusions and neurodegeneration, other features of tauopathies such as filamentous tau tangles were not observed. Future efforts to generate additional tau transgenic models should provide further insight into the molecular mechanisms and pathobiology of tauopathies.

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