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Secretion of amyloid precursor protein via signal transduction pathway

Research Project

Project/Area Number 06454705
Research Category

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

Allocation TypeSingle-year Grants
Research Field Neuroscience in general
Research InstitutionThe University of Tokyo

Principal Investigator

ISHIURA Shoichi  Institute of Molecular and Cellular Biosciences, The University of Tokyo, Associate Professor, 分子細胞生物学研究所, 助教授 (10158743)

Co-Investigator(Kenkyū-buntansha) SORIMACHI Hiroyuki  Institute of Molecular and Cellular Biosciences, The University of Tokyo, Assist, 分子細胞生物学研究所, 助手 (10211327)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1995: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1994: ¥4,700,000 (Direct Cost: ¥4,700,000)
KeywordsAlzheimer's disease / Amyloid / Signal transduction / C kinase / Secretion / アミロイドβ蛋白質
Research Abstract

Alzheimer's disease (AD) is characterized by progressive neurodegeneration. One of the features of AD is the formation of senile plaques, which contain mainly beta protein, small peptides comprising 39-43 amino acid residues, processed from a large membrane-bound amyloid precursor protein (APP). In AD brain, APP is converted to beta protein by abnormal processing, while almost all APP is normally secreted following cleavage of the precursor at amino acid 16 which falls within the beta protein molecule. This scission also leads to the retention of the residual C-terminal non-amyloidogenic 10 kDa fragment within the membrane. The regulation of beta protein formation by aberrant processing or of a secreted form by constitutive processing from the intact APP molecule remains unclear.
In order to study the mechanism of intracellular sorting and processing of the APP,we deleted two potential N-linked glycosylation sites, G-protein binding site, endosome-retension signal and lysosome-targeting signal of APP by site-directed mutagenesis. Wild-type and mutant APPs were expressed in COS-1 cells by cDNA transfection and the expression of the protein products and secretion of N-terminal large fragment was observed. The initial secretion of the mutant APP appeared to be slow compared with wild type.
The amount of APP secreted from PKC-transfected cells was higher than those from untransfected. These results suggest that PKC regulates the secretion of APP through a signaling pathway.

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Maruyma, K. ,: "Secretion of Alzheimer β/A4 protein(1-40)and intracellular retention β/A4 protein (1-42) in transfected COS cells." Biochem. Biophys. Res. Commum.207. 971-977 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ohsawa, I. ,: "Expression, purification, and neurotrophic activity of amyloid precurso protein-secreted forms produced by yeast." Biochem. Biophys. Res. Commum.213. 52-58 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Mantle, D. ,: "Comparison of cathepsin protease activities in brain tissue from normal cases and cases with Alzheimer's disease, Lewy body dementia,Parkinson's disease and Huntington's disease." J. Neurol. Sci.131. 65-70 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. Kinouchi,: "cPKα nad nPKε, but notδ, increase APP secretion from PKC cDNA transfected fibroblasts treated with TPA." FEBS Lett.364. 203-206 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. Yoshizawa,: "A catalytic subunit of calpain possesses full proteolytic activity." FEBS Lett.358. 101-103 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. Kinouchi,: "Arachidonate metabolites affect the secretion of N-terminal fragment of Alzheimer's disease amyloid precursor protein." Biochem. Biophys. Res. Commum.209. 841-849 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 石浦章一: "脳の老化はなぜ起こるか" 化学, 17-19 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 石浦章一: "アミロイド前駆体の分泌機構の解明「ブレインサイエンス最前線96」" 講談社サイエンティフィク, 95-106 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Maruyama, K.& Ishiura, S: "Secretion of Alzheimer beta/A4 protein (1-40) and intracellular retention of beta/A4 protein (1-42) in transfected COS cells." Biochem.Biophys.Res.Commun.207. 971-977 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ohsawa, I.& Ishiura, S.: "Expression, purification and neurotrophic activity of amyloid precursor protein-secreted forms produced by yeast." Biochem.Biophys.Res.Commun.213. 52-58 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Mantle, D.& Ishiura, S: "Comparison of cathepsin protease activities in brain tissue from normal cases and cases with Alzheimer's disease, Lewy body dementia, Parkinson's disease and Huntington's disease." J.Neurol.sci.131. 65-70 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kinouch, T.& Ishiura, S.: "cPK alpha and nPK epsilon, but not delta, increase APP secretion from PKC cDNA transfectfibroblasts treated with TPA." FEBS Lett.364. 203-206 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Yoshizawa, T.& Ishiura, S.: "A catalytic subunit of calpain possesses full proteolytic activity." FEBS Lett.358. 101-103 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kinouchi, T.&Ishiura S.: "Arachidonate metabolites affect the secretion of N-terminal fragment of Alzheimer's disease amyloid precursor protein." Biochem.Biophys.Res.Commun.209. 841-849 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Maruyama,K.,他: "Secretion of Alzheimer β/A4 protein(1-40)and intracellular retention of β/A4 protein(1-42)in transfected COS cells." Biochem.Biophys.Res.Commun.207. 971-977 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ohsawa,I.,他: "Expression,purification,and neurotrophic activity of amyloid precursor protein-secreted forms produced by yeast." Biochem.Biophys.Res.Commun.213. 52-58 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Mantle,D.,他: "Comparison of cathepsin protease activities in brain tissue from normal cases and cases with Alzheimer's disease,Lewy body dementia," J.Neurol.Sci.131. 65-70 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] T.Kinouchi,他: "cPKα and nPKε,but notδ,increase APP secretion from PKC cDNA transfected fibroblasts treated with TPA." FEBS Lett.364. 203-206 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] T.Yoshizawa,他: "A catalytic subunit of calpain possesses full proteolytic activity." FEBS Lett.358. 101-103 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] T.Kinouchi,他: "Arachidonate metabolites affect the secretion of N-terminal fragment of Alzheimer's disease amyloid precursor protein." Biochem.Biophys.Res.Commun.209. 841-849 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 石浦章一: "化学" 脳の老化はなぜ起こるか.50. 17-19 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 石浦章一: "アミロイド前駆体の分泌機構の解明「ブレインサイエンス最前線96」" 講談社サイエンテイフイク, 95-106 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Masaki,T.et al.: "Multicatalytic proteinase is associated with characteristic oval structures in cortical Lewy bodies:an immunocytochemical study with light and electron microscopy" J.NeurOl.Sci. 122. 127-134 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kinbara,k.et al.: "Processing and secretion of the amyloid precursor protein." Tohoku J.Exp.Med.174. 209-216 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Maruyama,k.et al.: "The cleavage at the N-terminalsite of Alzheimer amyloid b/A4 proteinis essential for its secretion" Biochem.Biophys.Res.Commun.202. 1517-1523 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Fukunari,A.et al.: "Colocalization of prolyl endopeptidase and amyloid-peptide in brains of senescence-accelerated mouse." Neurosci.Lett.176. 201-204 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Maruyama,K.et al.: "The toxic effect of Alzheimer amyloid protein precursor overexpressed in the neuroblastoma cell line NB-1 on neurite outgrowth." Gerontology. 40. 57-64 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Sakamoto,K.et al.: "Femtogram quantification of calpain-related molecules by specific PCR amplification:Application to human muscular dystrophy." Biomed.Res.15. 337-346 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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