Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation.
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.
Murakami
Tetsuro
T
Department of Neurology, Neuroscience, Biophysiological Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558 Japan.
Paitel
Erwan
E
Kawarabayashi
Takeshi
T
Ikeda
Masaki
M
Chishti
M Azhar
MA
Janus
Christopher
C
Matsubara
Etsuro
E
Sasaki
Atsushi
A
Kawarai
Toshitaka
T
Phinney
Amie L
AL
Harigaya
Yasuo
Y
Horne
Patrick
P
Egashira
Nobuaki
N
Mishima
Kenichi
K
Hanna
Amanda
A
Yang
Jing
J
Iwasaki
Katsunori
K
Takahashi
Mitsuo
M
Fujiwara
Michihiro
M
Ishiguro
Koichi
K
Bergeron
Catherine
C
Carlson
George A
GA
Abe
Koji
K
Westaway
David
D
St George-Hyslop
Peter
P
Shoji
Mikio
M
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*
D013654:Taurine