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 expression system with an autoregulatory transactivator loop that resulted in high expression of human G272V tau in neurons and in oligodendrocytes. We show that G272V tau can form filaments in murine oligodendrocytes. Electron microscopy established that the filaments were either straight or had a twisted structure; these were 17-20 nm wide and had a periodicity of approximately 75 nm. Filament formation was associated with tau phosphorylation at distinct sites, including the AT8 epitope 202/205 in vivo. Immunogold electron 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 inclusions were also identified by thioflavin-S fluorescent microscopy in oligodendrocytes and motor neurons. These results establish that expression of the G272V mutation in mice causes oligodendroglial fibrillary lesions that are similar to those seen in human tauopathies.
Götz
J
J
Division of Psychiatry Research, University of Zürich, August Forel Str. 1, 8008 Zürich, Switzerland. goetz@bli.unizh.ch
Tolnay
M
M
Barmettler
R
R
Chen
F
F
Probst
A
A
Nitsch
R M
RM
D000818:Animals; D002490:Central Nervous System / Q000473:pathology / Q000503:physiopathology* / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic / Q000002:abnormalities / Q000235:genetics / Q000378:metabolism; D008854:Microscopy, Electron; D009154:Mutation / Q000502:physiology*; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010766:Phosphorylation; D012995:Solubility / Q000187:drug effects; D013752:Tetracycline / Q000494:pharmacology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure
D015534:Trans-Activators; D016875:tau Proteins; D013752:Tetracycline