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Neurodegenerative diseases and protein folding governed by copper ion

Research Project

Project/Area Number 12672084
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Physical pharmacy
Research InstitutionTohoku University

Principal Investigator

MIURA Takashi  Tohoku University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学研究科, 講師 (30222318)

Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordsneurodegenerative diseases / Alzheimer's disease / metal / histidine / tyrosine / Raman spectroscopy / 鉄 / プリオン / 銅 / 折りたたみ
Research Abstract

1. Aggregation of amyloid β-peptide (Aβ), a key pathological event in Alzheimer's disease, has been shown in vitro to be profoundly promoted by Zn(II). This fact suggests that some factors in the normal brain protect Aβ from the Zn(II)-induced aggregation. In this study, it has been demonstrated that Cu(II) effectively inhibits the Aβ aggregation by competing with Zn(II) for histidine residues. The Raman spectrum of a metal-Aβ complex in the presence of both Zn(II) and Cu(II) shows that the cross-linking of Aβ through binding of Zn(II) to the Nτ atom of histidine is prevented by chelation of Cu(II) by the Nπ atom of histidine and nearby amide nitrogens. The inhibitory effect is strongest at a Cu/Aβ molar ratio of around four. Above this ratio, Cu(II) itself promotes the Aβ aggregation by binding to the phenolate oxygen of Tyr10. These results emphasize the importance of regulation of Cu(II) levels to inhibit Aβ aggregation, and are consistent with an altered metal homeostasis in Alzheimer's disease.
2. The Fe(III) ion binds to Aβ and induces significant aggregation of the peptide. In order to understand the role of Fe(III) in Aβ aggregation, the Fe(III)-binding mode of Aβ has been examined by Raman spectroscopy. The Raman spectra of Fe(III)-Aβ complexes excited at 514.5 nm are dominated by resonance Raman bands of metal-bound tyrosinate, evidencing that the Fe(III) ion primarily binds to Aβ via the phenolic oxygen of Tyr10. On the other hand, histidine ewsidues in the N-terminal hydrophilic region of Aβ do not bind to Fe(III). These results are in sharp contrast to the Zn(II)-induced aggregation of Aβ, in which histidine residues act as the primary metal binding sites.

Report

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

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Takashi Miura: "Binding mode of Congo Red to Alzheimer's amyloid β-peptide studied by Raman spectroscopy"Journal of Raman Spectroscopy. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takashi Miura: "Binding of Iron(III) to the Single Tyrosine Residue of Amyloid β-Peptide Probed by Raman Spectroscopy"Journal of Molecular Structure. 598(1). 79-84 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kiyoko Suzuki: "Inhibitory Effect of Copper(II) on Zinc(II)-Induced Aggregation of Amyloid β-Peptide"Biochemica Biophysica Research Communications. 285(4). 991-996 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takashi Miura: "Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes"Biochemistry. 39(23). 7024-7031 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takashi Miura: "Binding mode of Congo Red to Alzheimer's amyloid β-peptide studied by Raman spectroscopy"Journal of Raman Spectroscopy. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takashi Miura: "Binding of Iron(III) to the Single Tyrosine Residue of Amyloid β-Peptide Probed by Raman Spectroscopy"Journal of Molecular Structure. 598. 79-84 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kiyoko Suzuki: "Inhibitory Effect of Copper(II) on Zinc(II)-Induced Aggregation of Amyloid β-Peptide"Biochemical Biophysical Research Communications. 285. 991-996 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takashi Miura: "Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes"Biochemistry. 39. 7024-7031 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takashi Miura, Chiaki Yamamiya Miho Sasaki, et al.: "Binding mode of Congo Red to Alzheimer's amyloid β-peptide studied by Raman spectroscopy"Journal of Raman Spectroscopy. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takashi Miura, Kiyoko Suzuki & Hideo Takeuchi: "Binding of Iron(III) to the Single Tyrosine Residue of Amyloid β-peptide Probed by Raman Spectroscopy"Journal of Molecular Structure. 598(1). 79-84 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takashi Miura, Kiyoko Suzuki & Hideo Takeuchi: "Inhibitory Effect of Copper(II) on Zinc(II)-Induced Aggregation of Amyloid β-Peptide"Biochemica Biophysica Research Communications. 285(4). 991-996 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takashi Miura: "Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes"Biochemistry. 39(23). 7024-7031 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takashi Miura: "Binding of iron (III) to the single tyrosine residue of amyloid β-peptide probed by Raman spectroscopy"Journal of Molecular Structure. (in press). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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