P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating

Hiroki Takeuchi, Michiyo Iba, Haruhisa Inoue, Makoto Higuchi, Keizo Takao, Kayoko Tsukita, Yoshiko Karatsu, Yumiko Iwamoto, Tsuyoshi Miyakawa, Tetsuya Suhara, John Q. Trojanowski, Virginia M.Y. Lee, Ryosuke Takahashi

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions.

Original languageEnglish
Article numbere21050
JournalPloS one
Volume6
Issue number6
DOIs
Publication statusPublished - 20-06-2011

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Tauopathies
Sensory Gating
dementia
Transgenic Mice
signs and symptoms (animals and humans)
Dementia
tau Proteins
genetically modified organisms
mutants
mice
Alzheimer disease
Alzheimer Disease
testing
Prodromal Symptoms
animal models
Pathology
Mutant Proteins
Neurologic Manifestations
proteins
Neurodegenerative Diseases

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Takeuchi, Hiroki ; Iba, Michiyo ; Inoue, Haruhisa ; Higuchi, Makoto ; Takao, Keizo ; Tsukita, Kayoko ; Karatsu, Yoshiko ; Iwamoto, Yumiko ; Miyakawa, Tsuyoshi ; Suhara, Tetsuya ; Trojanowski, John Q. ; Lee, Virginia M.Y. ; Takahashi, Ryosuke. / P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. In: PloS one. 2011 ; Vol. 6, No. 6.
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abstract = "Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions.",
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Takeuchi, H, Iba, M, Inoue, H, Higuchi, M, Takao, K, Tsukita, K, Karatsu, Y, Iwamoto, Y, Miyakawa, T, Suhara, T, Trojanowski, JQ, Lee, VMY & Takahashi, R 2011, 'P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating', PloS one, vol. 6, no. 6, e21050. https://doi.org/10.1371/journal.pone.0021050

P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. / Takeuchi, Hiroki; Iba, Michiyo; Inoue, Haruhisa; Higuchi, Makoto; Takao, Keizo; Tsukita, Kayoko; Karatsu, Yoshiko; Iwamoto, Yumiko; Miyakawa, Tsuyoshi; Suhara, Tetsuya; Trojanowski, John Q.; Lee, Virginia M.Y.; Takahashi, Ryosuke.

In: PloS one, Vol. 6, No. 6, e21050, 20.06.2011.

Research output: Contribution to journalArticle

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T1 - P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating

AU - Takeuchi, Hiroki

AU - Iba, Michiyo

AU - Inoue, Haruhisa

AU - Higuchi, Makoto

AU - Takao, Keizo

AU - Tsukita, Kayoko

AU - Karatsu, Yoshiko

AU - Iwamoto, Yumiko

AU - Miyakawa, Tsuyoshi

AU - Suhara, Tetsuya

AU - Trojanowski, John Q.

AU - Lee, Virginia M.Y.

AU - Takahashi, Ryosuke

PY - 2011/6/20

Y1 - 2011/6/20

N2 - Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions.

AB - Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions.

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