Oligodendroglial tau filament formation in transgenic mice expressing G272V tau

Genetic evidence indicates that several mutations in tau, including G272V, are linked to frontotemporal dementia with parkinsonism. We expressed this mutation in mouse brains by combining a prion protein promoter-driven expre ssion system with an autoregulatory transactivator loop that resulted in hi gh expression of human G272V tau in neurons and in oligodendrocytes. We sho w that G272V tau can form filaments in murine oligodendrocytes. Electron mi croscopy established that the filaments were either straight or had a twist ed structure; these were 17-20 nm wide and had a periodicity of approximate to 75 nm, Filament formation was associated with tau phosphorylation at di stinct sites, including the AT8 epitope 202/205 in vivo. Immunogold electro n microscopy of sarcosyl-extracted spinal cords from G272V transgenic mice using phosphorylation-dependent antibodies AT8 or AT100 identified several sparsely gold-labelled 6-nm filaments. In the spinal cord, fibrillary inclu sions were also identified by thioflavin-S fluorescent microscopy in oligod endrocytes and motor neurons. These results establish that expression of th e G272V mutation in mice causes oligodendroglial fibrillary lesions that ar e similar to those seen in human tauopathies.