Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein

Coding region and intronic mutations in the tau gene cause frontotemporal d ementia and parkinsonism linked to chromosome 17. Some of these mutations l ead to an overproduction of tau isoforms with four microtubule-binding repe ats. Here we have expressed the longest four-repeat human brain tau isoform in transgenic mice under the control of the murine Thy1 promoter. Transgen ic mice aged 3 weeks to 25 months overexpressed human tau protein in nerve cells of brain and spinal cord. Numerous abnormal, tau-immunoreactive nerve cell bodies and dendrites were seen. In addition, large numbers of patholo gically enlarged axons containing neurofilament- and tau-immunoreactive sph eroids were present, especially in spinal cord. Signs of Wallerian degenera tion and neurogenic muscle atrophy were observed. When motor function was t ested, transgenic mice showed signs of muscle weakness. Taken together, the se findings demonstrate that overexpression of human four-repeat tau leads to a central and peripheral axonopathy that results in nerve cell dysfuncti on and amyotrophy.