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(American Journal of Pathology. 2005;166:521-531.)
© 2005 American Society for Investigative Pathology

Accumulation of Filamentous Tau in the Cerebral Cortex of Human Tau R406W Transgenic Mice

Masaki Ikeda^*, Mikio Shoji, Toshitaka Kawarai, Takeshi Kawarabayashi, Etsuro Matsubara, Tetsuro Murakami, Atsushi Sasaki^¶, Yasushi Tomidokoro^*, Yasushi Ikarashi^||, Hisashi Kuribara^**, Koichi Ishiguro, Masato Hasegawa, Shu-Hui Yen, M. Azhar Chishti, Yasuo Harigaya^¶¶, Koji Abe, Koichi Okamoto^*, Peter St. George-Hyslop and David Westaway

From the Department of Neurology,^* Department of Human Pathology,^¶ Gunma University Graduate School of Medicine, Gunma, Japan; the Department of Neurology, Neuroscience, Biophysiological Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan; the Centre for Research in Neurodegenerative Diseases, Departments of Medicine (Neurology) and Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, Ontario, Canada; the Department of Neurology,^¶¶ Maebashi Red Cross Hospital, Gunma, Japan; the Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan; the Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo, Japan; R&D Division,|| Tsumura & Co., Ltd., Ibaraki, Japan; the Laboratory of Development,^** Wakanyaku Medical Institute. Ltd., Gunma, Japan; and the Mayo Clinic Jacksonville, Jacksonville, Florida

Correspondence: Address correspondence to Masaki Ikeda, M.D., Ph.D., Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan, E-mail: mikeda{at}med.gunma-u.ac.jp

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-3ß 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).

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