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(American Journal of Pathology. 2006;169:1365-1375.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051250

Cortical Neuronal and Glial Pathology in TgTau^P301L Transgenic Mice

Neuronal Degeneration, Memory Disturbance, and Phenotypic Variation

Tetsuro Murakami^*, Erwan Paitel, Takeshi Kawarabayashi^*, Masaki Ikeda, M. Azhar Chishti, Christopher Janus, Etsuro Matsubara, Atsushi Sasaki^¶, Toshitaka Kawarai, Amie L. Phinney, Yasuo Harigaya^||, Patrick Horne, Nobuaki Egashira^**, Kenichi Mishima^**, Amanda Hanna, Jing Yang, Katsunori Iwasaki^**, Mitsuo Takahashi, Michihiro Fujiwara^**, Koichi Ishiguro, Catherine Bergeron, George A. Carlson, Koji Abe^*, David Westaway, Peter St. George-Hyslop and Mikio Shoji^*

From the Department of Neurology,^* Neuroscience and Biophysiological Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; the Department of Neurology and First Department of Pathology,^¶ Gunma University Graduate School of Medicine, Gunma, Japan; the Department of Alzheimer’s Disease Research, National Institute of Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan; the Department of Neurology,|| Maebashi Red Cross Hospital, Gunma, Japan; the Departments of Clinical Pharmacology and Neuropharmacology,^** Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; the Alzheimer’s Disease Group, Mitsubishi Kagaku Institute of Life Sciences, Tokyo, Japan; the Departments of Medicine (Neurology) and Laboratory Medicine and Pathobiology, Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada; and the McLaughlin Research Institute, Great Falls, Montana

Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTau^P301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTau^P301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTau^P301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTau^P301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy.