title: Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation.
abstract: 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.
authors.affiliation: Department of Neurology, Neuroscience, Biophysiological Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558 Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Murakami
authors.forename: Erwan
authors.initials: E
authors.lastname: Paitel
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawarabayashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Ikeda
authors.forename: M Azhar
authors.initials: MA
authors.lastname: Chishti
authors.forename: Christopher
authors.initials: C
authors.lastname: Janus
authors.forename: Etsuro
authors.initials: E
authors.lastname: Matsubara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sasaki
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Amie L
authors.initials: AL
authors.lastname: Phinney
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Harigaya
authors.forename: Patrick
authors.initials: P
authors.lastname: Horne
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Egashira
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mishima
authors.forename: Amanda
authors.initials: A
authors.lastname: Hanna
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Takahashi
authors.forename: Michihiro
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Koichi
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Catherine
authors.initials: C
authors.lastname: Bergeron
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Mikio
authors.initials: M
authors.lastname: Shoji
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry / Q000473:pathology*; D003704:Dementia / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005911:Gliosis / Q000473:pathology*; D006801:Humans; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D013654:Taurine / Q000032:analysis / Q000235:genetics*
chemical_list: D013654:Taurine