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Kinetic and thermodynamic analysis of the molecular interaction on amyloid fibril formation

Research Project

Project/Area Number 18570149
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biophysics
Research InstitutionUniversity of Fukui

Principal Investigator

HASEGAWA Kazuhiro  University of Fukui, Faculty of Medical Sciences, Assistant Professor (60324159)

Co-Investigator(Kenkyū-buntansha) NAIKI Hironobu  University of Fukui, Faculty of Medical Sciences, Professor (10227704)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,110,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsBiophysics / Biological molecules / Amyloid fibril / Alzheimaer's disease / Dialysis-related amyloidosis
Research Abstract

Amyloid is extracellular deposit of insoluble fibrillar aggregate of proteins those are normally soluble in their native conformation, resulting in the impairment of tissue structure and function. We have established several amyloid fibril formation systems in vitro, including β-amyloid of Alzheimer's disease (Aβ) and β2-microglobulin (β2-m) amyloid (Aβ2M) of dialysis-related amyloidosis. Using these systems, important roles of various biological molecules or compounds on the formation and dissociation of amyloid fibrils were discovered. To model the amyloid fibril formation in vivo by in vitro experimental system or numerical model, we selected several phases of fibril formation or dissociation, and clarified their mechanism by biophysical, kinetic and thermodynamic analyses.
1. To understand the molecular pathogenesis of Aβ2M amyloidosis, the biological molecules that induce amyloid fibril formation by affecting the conformation and stability of β2-m and amyloid fibrils need to be ide … More ntified. We showed that anionic amphipathic compounds including non-esterified fatty acids (NEFAs) and some lysophospholipids induce the fibril extension at a neutral pH. Furthermore, hemodialysis patients had significantly higher plasma concentrations of lysophospholipids than healthy subjects. These results suggest possible role of lysophospholipids and NEFAs in the development of Aβ2M amyloidosis.
2. Using spectrophotometry, spectrofluorometry and surface plasmon resonance, we investigated the anti-amyloidogenic effects of five flavonoids on β-amyloid fibril (fAβ) in vitro. The results suggest that flavonoids, especially myricetin exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fAβ, rather than to Aβ monomers.
3. We developed a high-throughput screening system for the nucleation of Aβ2M and Aβ amyloid fibril using thioflavin T fluorescence spectroscopy. Using this system, effect of various biological molecules including proteoglycans, glycosaminoglycans, were investigated. As the conclusion of this study, the remarkable advance in the clarification of the mechanism of Aβ2M and Aβ amyloid fibril formation were obtained. Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (16 results)

All 2007 2006 Other

All Journal Article (11 results) (of which Peer Reviewed: 4 results) Presentation (5 results)

  • [Journal Article] The anti-amyloidogenic effect is exerted against Alzheimer's β-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure.2007

    • Author(s)
      Hirohata, M., et. al.
    • Journal Title

      Biochemistry 46

      Pages: 1888-1899

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] A toxic monomeric conformer of the polyglutamine protein2007

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

      Nat. Struct. Mol. Biol. 14

      Pages: 332-340

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] 透析アミロイドーシスとβ2ミクログロブリン2007

    • Author(s)
      長谷川一浩, 他
    • Journal Title

      細胞工学 26

      Pages: 156-161

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] β2-ミクログロブリンアミロイド線維形成・沈着の分子機構2007

    • Author(s)
      山本 卓, 他
    • Journal Title

      透析会誌 40

      Pages: 1028-1030

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Journal Article] ポリフェノールがβアミロイド蛋白凝集に及ぼす抗アミロイド効果の分子機構解明2007

    • Author(s)
      廣畑 美枝, 他
    • Journal Title

      未病と抗老化 16

      Pages: 115-127

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Journal Article] The anti-amyloidogenic effect is exerted against Alzheimer's beta-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure2007

    • Author(s)
      Hirohata, M., Hasegawa, K., Tsutsumi-Yasuhara, S., Ohhashi, Y., Ookoshi, T., Ono, K., Yamada, M., Naiki, H
    • Journal Title

      Biochemistry 46(7)

      Pages: 1888-1899

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] A toxic monomeric conformer of the polyglutamine protein.2007

    • Author(s)
      Nagai, Y., Inui, T., Popiel, HA., Fujikake, N., Hasegawa, K., Urade, Y., Goto, Y., Naiki, H., Toda, T
    • Journal Title

      Nat. Struct. Mol. Biol 14(4)

      Pages: 332-340

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] The anti-amyloidogenic effect is exerted against Alzheimer's β-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure.2006

    • Author(s)
      Hirahata, M. et al.
    • Journal Title

      Biochemistry 46(7)

      Pages: 1888-1899

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Lysophospholipids Induce the Nucleation and Extension of β2-Microglobulin-Related Amyloid Fibrils at a Neutral pH

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

      Nephrol. Dial. Transplant. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Lysophospholipids Induce the Nucleation and Extension of β2-Microglobulin-Related Amyloid Fibrils at a Neutral pH

    • Author(s)
      Ookoshi, T., Hasegawa, K., Ohhashi, Y., Kimura, H., Takahashi, N., Yoshida, H., Miyazaki, R., Goto, Y., Naiki, H
    • Journal Title

      Nephrol. Dial. Transplant (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Lysophospholipids Induce the Nucleation and Extension of β2-microglobulin-Related Amyloid Fibrils at a Neutral pH

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

      Nephrol. Dial. Transplant. (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] リゾリン脂質によるβ2-ミクログロブリンアミロイド線維伸長促進効果の解析2007

    • Author(s)
      大越 忠和, 他
    • Organizer
      第96回日本病理学会総会
    • Place of Presentation
      大阪市
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Polyphenolsがβアミロイド線維に及ぼす抗アミロイド効果の分子機構解明2007

    • Author(s)
      廣畑 美枝, 他
    • Organizer
      第48回日本神経学会総会
    • Place of Presentation
      名古屋
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] polyphenolsがβアミロイド線維に及ぼす抗アミロイド効果の分子機構解明2007

    • Author(s)
      廣畑 美枝, 他
    • Organizer
      第48回日本神経学会総会
    • Place of Presentation
      名古屋
    • Related Report
      2007 Annual Research Report
  • [Presentation] β2-ミクログロブリンアミロイド線維を伸長させるリゾリン脂質の探索2006

    • Author(s)
      大越 忠和, 他
    • Organizer
      第95回日本病理学会総会
    • Place of Presentation
      東京都
    • Year and Date
      2006-04-30
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] フラボノイドによるアルツハイマー病βアミロイド線維形成阻害機構2006

    • Author(s)
      長谷川一浩, 他
    • Organizer
      日本分子イメージング学会設立総会
    • Place of Presentation
      京都
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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