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2000 Fiscal Year Final Research Report Summary

Animal Model for Evaluation of Druge on Therapeutics of Alzheimer Disease

Research Project

Project/Area Number 09470208
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionOsaka University

Principal Investigator

TAKEDA Masatoshi  Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (00179649)

Co-Investigator(Kenkyū-buntansha) TANAKA Toshihisa  Osaka University Graduate School of Medicine, Assiatant Professor, 医学系研究科, 助手 (10294068)
NAKAMURA Yu  Osaka University Graduate School of Medicine, Assiatant, 医学系研究科, 助手 (70291440)
KUDO Takashi  Osaka University Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (10273632)
TAKEDA Junji  Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (50163407)
Project Period (FY) 1997 – 2000
KeywordsAlzheimer Disease / Presenilin / Endoplasmic Reticulum / Aging / Aβ(Amyloid β) / GFAP (Grially Fibrillary Acidic Protein)
Research Abstract

We succeeded in making a knock-in mouse model that has mutant presenilin-1 gene (I213T). An increase of the ratio of Aβ42/Aβ40 was observed in this model mouse. Immunohistochemical study showed no senile plaque or no neurofibrillary tangle in this mouse in 30 weeks, 8 months, and 24 months, however an increase of anti-GFAP antibody-positive astrocytes was observed in hippocampus of this model mouse in the gene-dose dependent manner. An increase of anti-GFAP antibody staining was also observed in Western bolt analysis. Furthermore an increase of intracellular Aβ42 was observed in neurons was observed in the II and III layers of cerebral cortex. These results suggest that PS-1 mutation and aging synergetically induce increase of astrocytes and accumulation of intracellular Aβ42 that are usually observed in Alzheimer brains.
Primary cultured neurons derived from this model mouse showed decreased responses to ER (endoplasmic reticulum) stresses. The expression of GRP78, one of chaperone protein, was decreased and Ire 1, an sensor protein to ER stress, was less functioning, in cells with expression of mutant presenilin. Therefore apoptosis was more easily induced in these cells than in cells without mutant presenilin. A part of mechanisms on neurodegeneration in mutant presenilin was clarified.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Morihara,T. et al: "Increased tau prorein level in postmortem cerebrospinal fluid."Psychiat.Clin.Neurosci.. 52. 107-110 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanimukai,H et al: "Alzheimer-associated presenilin 1 gene is induced in gerbil hippocampus after transient ischemia."Mol Brain Res. 54. 212-218 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakano,Y. et al: "Accumulation of murine amyloid beta 42 with a gene-dosage dependent manner in PS1 ′knock-in′ mice."Eur J Neurosci. 11. 1-5 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Katayama,T. et al: "Presenilin-1 Mutations Downregulate the Signalling Pathway of Unfolded-protein Response."Nature Cell Biol. 1. 479-485 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takashi Kudo et al: "Are cerebrovascular factors involved in Alzheimer's disease?"Neurobio.Aging. 21. 215-224 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ichiro Tsujio et al: "Inactivation of glycogen synthase kinase-3 by protein kinase C δ : Implications on regulation of τ phosphorylation"FEBS lett. 469(1). 111-117 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Morihara, T.et al: "Increased tau prorein level in postmortem cerebrospinal fluid."Psychiat.Clin.Neurosci.. 52. 107-110 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanimukai, H et al: "Alzheimer-associated presenilin 1 gene is induced in gerbil hippocampus after transient ischemia"Mol Brain Res. 54. 212-218 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakano, Y.et al: "Accumulation of murine amyloid beta 42 with a gene-dosage dependent manner in PS1 'knock-in' mice."Eur J Neurosci. 11. 1-5 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Katayama, T.et al: "Presenilin-1 Mutations Downregulate the Signalling Pathway of Unfolded-protein Response."Nature Cell Biol. 1. 479-485 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takashi Kudo et al: "Are cerebrovascular factors involved in Alzheimer's disease?"Neurobio. Aging. 21. 215-224 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ichiro Tsujio et al: "Inactivation of glycogen synthase kinase-3 by protein kinase Cδ : Implications on regulation of τ phosphorylation"FEBS lett. 469(1). 111-117 (2000)

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

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Published: 2002-03-26  

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