title: Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice.
abstract: Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).
authors.affiliation: Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. mikeda@med.gunma-u.ac.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Ikeda
authors.forename: Mikio
authors.initials: M
authors.lastname: Shoji
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawarabayashi
authors.forename: Etsuro
authors.initials: E
authors.lastname: Matsubara
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Murakami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sasaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tomidokoro
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ikarashi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kuribara
authors.forename: Koichi
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Yen
authors.forename: M Azhar
authors.initials: MA
authors.lastname: Chishti
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Harigaya
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: David
authors.initials: D
authors.lastname: Westaway
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D006224:Cricetinae; D005822:Genetic Vectors; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D008854:Microscopy, Electron; D009154:Mutation; D020125:Mutation, Missense; D010766:Phosphorylation; D011328:Prions / Q000378:metabolism; D011487:Protein Conformation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019076:Transgenes; D025801:Ubiquitin / Q000378:metabolism; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D011328:Prions; D025801:Ubiquitin; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3