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2004 Fiscal Year Final Research Report Summary

Hyperphosphorylation and aggregation of tau protein, and neuronal death

Research Project

Project/Area Number 12210005
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionUniversity of Tokyo

Principal Investigator

IHARA Yasuo  University of Tokyo, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (60114386)

Co-Investigator(Kenkyū-buntansha) MORISHIMA Maho  University of Tokyo, Graduate School of Medicine, Lecturer, 大学院医学系研究科, 講師 (50204722)
FUNAMOTO Satoru  University of Tokyo, Graduate School of Medicine, Instructor, 大学院医学系研究科, 助手 (10345043)
MIYASAKA Tomohiro  University of Tokyo, Graduate School of Medicine, Instructor, 大学院医学系研究科, 助手 (90342857)
ITO Mamoru  University of Tokyo, Graduate School of Medicine, Senior Scientist, 免疫研究室, 室長 (00176364)
FUJITA Shinobu  Mitsubishi Kagaku Inst., Life Sciences, Senior Researcher, 生命科学研究所, 主任研究員 (30092323)
Project Period (FY) 2000 – 2004
KeywordsAlzheimer's disease / Tau / Neurofibrillary tangles / Neuronal death
Research Abstract

Discovery of various mutations in the tau gene among the families affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) suggests gain-of-toxic function of wild-type or mutant tau as the mechanism for extensive neuronal loss. To learn about the role of tau in the tauopathy, we have generated animal models that express FTDP-17 mutant (P301L or R406W) tau.
1.We established transgenic mice expressing prion promoter-driven P301L mutant tau. The brains were sampled from those mice at various ages (3, 6, 12, 20, and 24 months) and analyzed by either biochemical or immunohistochemical methods. However, transgene-derived alterations, such as degeneration of neurons and deposition of tau, were not observed up to 24 months.
2.We generated transgenic nematode (Caenorhabditis elegans) expressing wild-type or mutant (P301L and R406W) tau in the touch (mechanosensory) neurons. Whereas the worm expressing wild-type tau showed only a small decrease in the touch response across the lifespan, the worm expressing mutant tau displayed a large and progressive decrease. When the touch neurons lost their function, neuritic abnormalities were prominent, and microtubular loss became remarkable in the later stage. A substantial fraction of degenerating neurons developed tau accumulation in the cell body and neuronal processes. This neuronal dysfunction is not related to the apoptotic process because little recovery from touch abnormality was observed in the ced-3 or ced-4-deficient background. Expression of GSK3 brought about slight deterioration in the touch response, while expression of HSP70 led to some improvement.

  • Research Products

    (42 results)

All 2005 2004 2003 2001 2000

All Journal Article (42 results)

  • [Journal Article] Longer forms of amyloid β-protein : implications for the mechanism of intramembranous cleavage by γ-secretase.2005

    • Author(s)
      Qi-Takahara Y, et al.
    • Journal Title

      J Neurosci 25

      Pages: 436-445

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Independent accumulations of tau and amyloid β-protein in the human entorhinal cortex.2005

    • Author(s)
      Katsuno T, et al.
    • Journal Title

      Neurology 64

      Pages: 687-692

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Progressive neurodegeneration in C. elegans model of tauopathy.2005

    • Author(s)
      Miyasaka T, et al.
    • Journal Title

      Neurobiol Dis 20

      Pages: 372-383

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Blocking the cleavage at midportion between γ- and ε-sites remarkably suppresses the generation of amyloid β-protein.2005

    • Author(s)
      Sato T, et al.
    • Journal Title

      FEBS Lett 579

      Pages: 2907-2912

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Visualization of newly deposited tau in neurofibrillary tangles and neuropil threads.2005

    • Author(s)
      Miyasaka T, et al.
    • Journal Title

      J Neuropathol Exp Neurol 64

      Pages: 665-674

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Longer forms of amyloid β-protein : implications for the mechanism of intramembranous cleavage by y-secretase.2005

    • Author(s)
      Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Hirotani N, Horikoshi Y, Maeda M, Saido TC, Ihara Y
    • Journal Title

      J Neurosci 25

      Pages: 436-445

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Independent accumulations of tau and amyloid β-protein in the human entorhinal cortex.2005

    • Author(s)
      Katsuno T, Morishima-Kawashima M, Saito Y, Yamanouchi H, Ishiura S, Murayama S, Ihara Y
    • Journal Title

      Neurology 64

      Pages: 687-692

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Progressive neurodegeneration in C.elegans model of tauopathy.2005

    • Author(s)
      Miyasaka T, Ding Z, Gengyo-Ando K, Oue M, Yamaguchi H, Mitani S, Ihara Y
    • Journal Title

      Neurobiol Dis 20

      Pages: 372-383

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Blocking the cleavage at midportion between γ- and ε-sites remarkably suppresses the generation of amyloid β-protein.2005

    • Author(s)
      Sato T, Tanimura Y, Hirotani N, Saido TC, Morishima-Kawasdhima M, Ihara Y
    • Journal Title

      FEBS Lett 579

      Pages: 2907-2912

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Visualization of newly deposited tau in neurofibrillary tangles and neuropil threads.2005

    • Author(s)
      Miyasaka T, Watanabe A, Saito Y, Murayama S, Mann DMA, Yamazaki M, Ravid R, Morishima-Kawashima M, Nagashima K, Ihara Y
    • Journal Title

      J Neuropathol Exp Neurol 64

      Pages: 665-674

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Gem GTPase and tau : morphological changes induced by Gem GTPase in CHO cells are antagonized by tau.2004

    • Author(s)
      Oyama F, et al.
    • Journal Title

      J Biol Chem 279

      Pages: 27272-27277

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Molecular aging of tau : disulfide-independent aggregation and nonenzymatic degradation in vitro and in vivo.2004

    • Author(s)
      Watanabe A, et al.
    • Journal Title

      J Neurochem 90

      Pages: 1302-1311

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Truncated carboxyl terminal fragments of β-amyloid precursor protein are processed to amyloid β-proteins 40 and 42.2004

    • Author(s)
      Funamoto S, et al.
    • Journal Title

      Biochemistry 43

      Pages: 13532-13540

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Gem GTPase and tau : morphological changes induced by Gem GTPase in CHO cells are antagonized by tau.2004

    • Author(s)
      Oyama F, Kotliarova S, Harada A, Ito M, Miyazaki H, Ueyama Y, Hirokawa N, Nukina N, Ihara Y
    • Journal Title

      J Biol Chem 279

      Pages: 27272-27277

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Molecular aging of tau : disulfide-independent aggregation and nonenzymatic degradation in vitro and in vivo.2004

    • Author(s)
      Watanabe A, Hong W-K, Dohmae N, Takio K, Morishima-Kawashima M, Ihara Y
    • Journal Title

      J Neurochem 90

      Pages: 1302-1311

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Truncated carboxyl terminal fragments of β-amyloid precursor protein are processed to amyloid Β-proteins 40 and 42.2004

    • Author(s)
      Funamoto S, Morishima-Kawashima M, Tanimura Y, Hirotani N, Saido TC, Ihara Y
    • Journal Title

      Biochemistry 43

      Pages: 13532-13540

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid β-protein 42 in Chinese hamster ovary cells.2003

    • Author(s)
      Qi Y, et al.
    • Journal Title

      Biochemistry 42

      Pages: 1042-1052

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Potential link between amyloid β-protein 42 and C-terminal fragment γ49-99 of β-amyloid precursor protein.2003

    • Author(s)
      Sato T, et al.
    • Journal Title

      J Biol Chem 278

      Pages: 24294-24301

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] γ-Secretase activity is present in rafts, but not cholesterol-dependent.2003

    • Author(s)
      Wada S, et al.
    • Journal Title

      Biochemistry 42

      Pages: 13977-13986

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid β-protein 42 in Chinese hamster ovary cells.2003

    • Author(s)
      Qi Y, Morishima-Kawashima M, Sato T, Mitsumori R, Ihara Y
    • Journal Title

      Biochemistry 42

      Pages: 1042-1052

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Potential link between amyloid β-protein 42 and C-terminal fragment γ49-99 of β-amyloid precursor protein.2003

    • Author(s)
      Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, Maruyama H, Koo EH, Haass C, Takio K, Morishima-Kawashima M, Ishiura S, Ihara Y
    • Journal Title

      J Biol Chem 278

      Pages: 24294-24301

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] γ-Secretase activity is present in rafts, but not cholesterol-dependent.2003

    • Author(s)
      Wada S, Morishima-Kawashima M, Qi Y, Misono H, Shimada Y, Ohno-Iwashita Y, Ihara Y
    • Journal Title

      Biochemistry 42

      Pages: 13977-13986

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Molecular analysis of mutant and wild-type tau deposited in the brain affected by FTDP-17 R406W mutation.2001

    • Author(s)
      Miyasaka T, et al.
    • Journal Title

      Am J Pathol 158

      Pages: 373-379

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Accumulation and aggregation of amyloid β-protein in late endosomes of Niemann-Pick Type C cells.2001

    • Author(s)
      Yamazaki T, et al.
    • Journal Title

      J Biol Chem 276

      Pages: 4454-4460

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Accumulation of amyloid β-protein in the low-density membrane domain accurately reflects the extent of β-amyloid deposition in the brain.2001

    • Author(s)
      Oshima N, et al.
    • Journal Title

      Am J Pathol 158

      Pages: 2209-2218

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Selective deposition of mutant tau in the FTDP-17 brain affected by the P301L mutation.2001

    • Author(s)
      Miyasaka T, et al.
    • Journal Title

      J Neuropathol Exp Neurol 60

      Pages: 872-884

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Distinct intramembrane cleavage of the β-amyloid precursor protein family resembling γ-secretase-like cleavage of Notch.2001

    • Author(s)
      Gu Y, et al.
    • Journal Title

      J Biol Chem 276

      Pages: 35235-35238

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Molecular analysis of mutant and wild-type tau deposited in the brain affected by FTDP-17 R406W mutation.2001

    • Author(s)
      Miyasaka T, Morishima-Kawashima M, Ravid R, Heutink P, van Swieten JC, Nagashima K, Ihara Y
    • Journal Title

      Am J Pathol 158

      Pages: 373-379

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Accumulation and aggregation of amyloid β-protein in late endosomes of Niemann-Pick Type C cells.2001

    • Author(s)
      Yamazaki T, Chang TY, Haass C, Ihara Y
    • Journal Title

      J Biol Chem 276

      Pages: 4454-4460

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Accumulation of amyloid beta-protein in the low-density membrane domain accurately reflects the extent of beta-amyloid deposition in the brain.2001

    • Author(s)
      Oshima N, Morishima-Kawashima M, Yamaguchi H, Yoshimura M, Sugihara S, Khan K, Games D, Schenk D, Ihara Y
    • Journal Title

      Am J Pathol 158

      Pages: 2209-2218

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Selective deposition of mutant tau in the FTDP-17 brain affected by the P301L mutation.2001

    • Author(s)
      Miyasaka T, Morishima-Kawashima M, Ravid R, Kamphorst W, Nagashima, K, Ihara Y
    • Journal Title

      J Neuropathol Exp Neurol 60

      Pages: 872-884

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Distinct intramembrane cleavage of the β-amyloid precursor protein family resembling y-secretase-like cleavage of Notch.2001

    • Author(s)
      Gu Y, Misonou H, Sato T, Dohmae N, Takio K, Ihara Y
    • Journal Title

      J Biol Chem 276

      Pages: 35235-35238

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Oxidative stress induces intracellular accumulation of amyloid β-protein (Aβ) in human neuroblastoma cells.2000

    • Author(s)
      Misonou H, et al.
    • Journal Title

      Biochemistry 39

      Pages: 6951-6959

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Neurofibrillary tangle-associated collapsin response mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509, Ser-518 and Ser-522.2000

    • Author(s)
      Gu Y, et al.
    • Journal Title

      Biochemistry 39

      Pages: 4267-4275

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Evidence that collapsin response mediator protein-2 (CRMP-2) is involved in the dynamics of microtubules.2000

    • Author(s)
      Gu Y, et al.
    • Journal Title

      J Biol Chem 275

      Pages: 17917-17920

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mutant-presenilin 2-transgenic mice : A large increase in the levels of Aβ42 is presumably associated with the low-density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin.2000

    • Author(s)
      Sawamura N, et al.
    • Journal Title

      J Biol Chem 275

      Pages: 27901-27908

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Effect of apolipoprotein E allele ε4 on the initial phase of amyloid β-protein accumulation in the human brain.2000

    • Author(s)
      Morishima-Kawashima M, et al.
    • Journal Title

      Am J Pathol 157

      Pages: 2093-2099

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Oxidative stress induces intracellular accumulation of amyloid β-protein (Aβ) in human neuroblastoma cells.2000

    • Author(s)
      Misonou H, Morishima-Kawashima M, Ihara Y
    • Journal Title

      Biochemistry 39

      Pages: 6951-6959

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Neurofibrillary tangle-associated collapsin response mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509, Ser-518 and Ser-522.2000

    • Author(s)
      Gu Y, Hamajima N, Ihara Y
    • Journal Title

      Biochemistry 39

      Pages: 4267-4275

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Evidence that collapsin response mediator protein-2 (CRMP-2) is involved in the dynamics of microtubules.2000

    • Author(s)
      Gu Y, Ihara Y
    • Journal Title

      J Biol Chem 275

      Pages: 17917-17920

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Mutant-presenilin 2-transgenic mice : A large increase in the levels of Aβ42 is presumably associated with the low-density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin.2000

    • Author(s)
      Sawamura N, Morishima-Kawashima M, Waki H, Kobayashi K, Kuramochi T, Ito M, Oyama F, Ando S, Ihara Y
    • Journal Title

      J Biol Chem 275

      Pages: 27901-27908

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Effect of apolipoprotein E allele ε4 on the initial phase of amyloid β-protein accumulation in the human brain.2000

    • Author(s)
      Morishima-Kawashima M, Oshima N, Ogata H, Yamaguchi H, Yoshimura M, Sugihara S, Ihara Y
    • Journal Title

      Am J Pathol 157

      Pages: 2093-2099

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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