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Mebiianism of neuronal cell death in Alzheimer disease. - AD analysis of signal transduction.

Research Project

Project/Area Number 11670617
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionFukui Medical University

Principal Investigator

KURIYAMA Masaru  Fukui Medical University.Umversity HoSpital,Professsor, 医学部, 教授 (80107870)

Co-Investigator(Kenkyū-buntansha) FUJIYAMA Jiro  Fukui Medical University.Umversity HoSpital,Professsor, 医学部・附属病院, 助手 (40283171)
MUTO Tatsuro  Fukui Medical University,Medical Department,Lectiire, 医学部・附属病院, 講師 (60190857)
平山 幹夫 (平山 幹生)  福井医科大学, 医学部, 助教授 (30181192)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsAmyloid β protein / apppoposis / PC12 / Tyrosine Kinase / Trk / phosphorylation / リン酸化反応 / TrKA / TrKB
Research Abstract

1) The neurotoxicity of amyloid β protein (a-β) : The fibrfflar form of a-β induced the tyrosine autophosphorylation of the Trk protein in PC12 cells. The reaction peaked at 10 mins and returned at 60 mins. The MAPK and Akt kinase in the downstream of Trk were also transiently activated. These reactions seemed to be a protective reaction.
2) The effect of PS1 mutation to the intraceUar signal transduction through Trk. : The Trk phosphorylation by NGF was markedly decreased in the neuroblastoma cell line overexpressed mutated-PSl or wild type-PS l. EspeciaUy in the cells overexressed mutated-PSl, the immunoreactivity to Trk protein could not be found on the cell membrane, but in the cytosol, by a confocal microscopy, showing that the post translational modification or intracellar translocation of the Trk protein was disturbed in the cells. The experiments using ganglioside GMl-defective cells (NG-CR72 cells) showed that gangliosides had an important function for the localization of Trk protein.
3) The effect of HMG-CoA reductase inhibitor (statin) to the aggregation of a-β : The aggregation or elongation of a-β was examined by the method using fluorescent dye, tioflavine T. All statins except simvastatin inhibited the aggregation of a-β. As this inhibition could be found at very high concentration of statins, it was not thought that the dose of statins clinically used can block the formation of amyloid plaque in the brain.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Mutoh T, et al.: "Involvement of tyrosine phosphorylation and in HMG-CoA reductase inhibitor-induced cell death of L6 myoblasts"FEBS Lett.. 444. 85-89 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mutoh T. et al.: "Role of tyrosine phosphorylation of phospholipase C-γ1 in the signal transduction path way of HMG-CoA reductase inhibitor-induced cell death in L6 myoblasts"FEBS Lett. 446. 91-94 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mutoh T, et al.: "Unglycosylated Trk protein does not colocalize nor associate with ganglioside GMI in stable clone overexpressing Trk of PC12 cells (PCtrK)"Glycoconj J. 17. 233-237 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mutoh, T et al.: "Decreased phosphorylation levels of TrkB neurotrophin receptor in the spinal cords from patients with amyotrophin lateral sclerosis"Neurochem Res. 25. 239-245 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kumano T, et al.: "HMG-CoA reductase inhibitor induces a transient activaton of high affinity nerve growth factor receptor, trk, and morphological differentiation with fatal outcome in PC12 cells"Brain Res. 859. 169-172 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakawgawa H, et al.: "Tyrosine phosphorylation of the catalytic subunit p110 of phosphatidylinositol-3 kinase induced by HMG-CoA reductase inhibitor inhibits its kinase activity in L6 myoblasts"FEBS Lett. 508. 53-56 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mutoh, T., Kumano, T., Nakagawa, H., Kun'yama, M.: "Involvement of tyrosine phosphorylation and in HMG-CoA reductase inhibitor - induced cell death of L6 myoblasts."FEBS Lett.. 444. 85-89 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mutoh, T., Kumano, T., Nakagawa, H., Kuriyama, M: "Role of tyrosine phosphorylation of phospholipase C-γ 1 in the signal transduction pathway of HMG-CoA reductase inhibitor -induced cell death in L6 myoblasts."FEBS Lett.. 446. 91-94 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mutoh, T., Hamano, T., Tokuda, A., Kuriyama, M.: "Unglycosylated Trk protein does not colocalize nor associate with ganglioside GM1 in stable clone overexpressing Trk of PC12 cells (PCtrk)."PC12 cells (PCtrk).. 17. 233-237 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mutoh, T.,Sobue, G., Hamano, T., Kuriyama, M., Hirayama, M., Yamamoto, M., Mitsuma, T.: "Decreased phosphorylation levels of TrkB neurotrophin receptor in the spinal cords from patients with amyotrophic lateral sclerosis."Neurochem Res. 25. 239-245 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kumano, T., Mutoh, T., Nakagawa, H., Kuriyama, M.: "MG-CoA reductase inhibitor induces a transient activation of high affinity nerve growth factor receptor, trk, and morphological differentiation with fatal outcome in PC12 cells."Brain Res.. 859. 169-72 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirayama, M, Kuriyama, M.: "MK-801 is cytotoxic to microglia in vitoro and its cytotoxicity is attenuated by glutamate other excitotoxic agents and atropine Possible presence of glutamate receptor and muscariic receptor on microglia."Brain Res. 897. 204-206 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakagawa, H, Mutoh, T, Kumano, T, Kuriyama, M.: "Tyrosine phosphorylation of the catalytic subunit p11O of phosphatidylinositol-3 kinase induced by HMG-CoA reductase inhibitor inhibits its kinase activity in L6 myoblasts."hibitor inhibits its kinase activity in L6 myoblasts.. FEES Let. 53-56 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirayama M, et al.: "Improvement of apraxia of eyelid opening by wearing goggles"Lancet. 356. 1413 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mutho T, et al.: "Unglycosylated Trk protein does not colocalize nor associate with ganglioside GMI in stable clone overexpressing Trk of PC12 cells (PCtrk)"Glycoconjugate Journal. 17. 233-237 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mutho T, et al.: "Decreased phosphorylation levels of Trk B neurotrophin receptor in the spinal cords from patients with amyotrophic lateral sclerosis"Neurochemical Research. 25. 239-245 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hirayama M, et al.: "MK-801 is cytotoxic to microglia in vitro and its cytotoxivity is attenuated by glutamate, other excitotoxic agents and atropine Possible presence of glutamate receptor and muscarinic receptor on microglia"Brain Research. 897. 204-206 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hamano T, et al.: "Spinal Cavitous Hemorrhagic Infarction with Abdominal Aortic Aneurysm"European Journal of Neurology. 46. 160-162 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakagawa H, et al.: "Tyrosine phosphorylation of the catalytic subunit pllo of phospratidylinositol-3 kinase induced by HMG-CoA reductase inhibitor inhibits its kinase activity in L6 myoblasts"Febs Letters. 508. 53-56 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukutani Y, et al: "Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia"Psychiatry and Clinical Neurosciences. 53. 425-428 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoneda M, et al: "Vasogenic emeda on MELAS : A serial Study with diffusion-weighted MR imaging"NEUROLOGY. 53. 2182-2184 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kumano T, et al: "HMG-CoA reductase inhibitor induces a transient activation of high affinity nerve growth factor recepter, Trk, and morphological differentiation with fatal outcome in PC12 cells"Brain Research. 859. 169-172 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hamano T, et al: "Phosphoglycerate kinase deficiency : An adult myopathic form with a novel mutation"NEUROLOGY. 54. 1188-1190 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mutoh T, et al.: "Role of tyrosin phoshorylation of phospholipasecrl in the signaling pathway of HMGCoA reductase inhibitor-induced cell death"FEBS Letter. 446. 91-94 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mutoh T, et al.: "Involvement of tyrosine phosphorylation in HMG-CoA reductase inhibitor-induced cell death in L6 myoblasts."FEBS Letter. 444. 85-89 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Pitto M, et al.: "Influence of endogenous GMI ganglioside on TrkB activity in cuetured neurons."FEBS Letter. 439. 93-96 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakagawa H, et al.: "HMG-CoA reductase inhibitor-induced L6 myoblaot cell denth invdement of the phosphotdjlinsitol 3-kinase pathay"FEBS Letter. 438. 289-292 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mutoh T, et al.: "Glucosylceramide synthase inhibitor inhibits the action of nerve growth factor in PC12 cells."J Biol, Chem. 273. 26001-26007 (1998)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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