Tau filament formation in transgenic mice expressing P301L tau

Mutations in the microtubule-associated protein tau, including P301L, are g enetically coupled to hereditary frontotemporal dementia with parkinsonism linked to chromosome 17, To determine whether P301L is associated with fibr il formation in mice, we expressed the longest human tau isoform, human tau 40, with this mutation in transgenic mice by using the neuron-specific mous e Thy1.2 promoter. We obtained mice with high expression of human P301L tau in cortical and hippocampal neurons. Accumulated tau was hyperphosphorylat ed and translocated from axonal to somatodendritic compartments and was acc ompanied by astrocytosis and neuronal apoptosis indicated by terminal deoxy nucleotidyl transferase-mediated biotinylated dUTP nick end-labeling staini ng. Moreover, P301L tau formed abnormal filaments. Electron microscopy of s arcosyl-insoluble protein extracts established that the filaments had a str aight or twisted structure of variable length and were similar to 15 nm wid e. Immunoelcecton microscopy showed that the tau filaments were phosphoryla ted at the TG3, AT100, AT8, and AD199 epitopes in vivo. In cortex, brain st em, and spinal cord, neurofibrillary tangles were also identified by thiofl avin-S fluorescent microscopy and Gallyas silver stains. Together, our resu lts show that expression of the P301L mutation in mice causes neuronal lesi ons that are similar to those seen in human tauopathies.