Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice.
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).
Ikeda
Masaki
M
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
Shoji
Mikio
M
Kawarai
Toshitaka
T
Kawarabayashi
Takeshi
T
Matsubara
Etsuro
E
Murakami
Tetsuro
T
Sasaki
Atsushi
A
Tomidokoro
Yasushi
Y
Ikarashi
Yasushi
Y
Kuribara
Hisashi
H
Ishiguro
Koichi
K
Hasegawa
Masato
M
Yen
Shu-Hui
SH
Chishti
M Azhar
MA
Harigaya
Yasuo
Y
Abe
Koji
K
Okamoto
Koichi
K
St George-Hyslop
Peter
P
Westaway
David
D
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*
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