Cortical neuronal and glial pathology in TgTauP301L 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 IshiguroCatherine Bergeron, George A. Carlson, Koji Abe, David Westaway, Peter St. George-Hyslop, Mikio Shoji

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60 Citations (Scopus)


Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L 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 TgTauP301L 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 TgTauP301L 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.

Original languageEnglish
Pages (from-to)1365-1375
Number of pages11
JournalAmerican Journal of Pathology
Issue number4
Publication statusPublished - Oct 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine


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