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アミロイド線維形成を引き起こす生体内分子環境の解明

Research Project

Project/Area Number 18031014
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Science and Engineering
Research InstitutionUniversity of Fukui

Principal Investigator

内木 宏延  University of Fukui, 医学部, 教授 (10227704)

Co-Investigator(Kenkyū-buntansha) 長谷川 一浩  福井大学, 医学部, 助教 (60324159)
大越 忠和  福井大学, 医学部, 助教 (90362037)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥12,200,000 (Direct Cost: ¥12,200,000)
Fiscal Year 2007: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2006: ¥5,600,000 (Direct Cost: ¥5,600,000)
Keywordsアミロイド線維 / β2-ミクログロブリン / アルツハイマー病 / 透析アミロイド症 / 分子間相互作用
Research Abstract

アミロイド線維は、蛋白質が異常な立体構造をとり線維を形成したものである。これまでにアルツハイマー病βアミロイド線維(fAβ)、及びβ2-ミクログロブリン(β2-m)アミロイド線維等について、試験管内線維形成反応系を開発している。本研究ではこれらの反応系を用い、(1)種々の生体分子がアミロイド線維形成を促進・阻害する分子機構を、生体分子間相互作用の解析を通して疾病発症機構(医学)の観点から明らかにすること、及び、(2)種々の有機化合物による線維形成阻害・分解の分子機構の解明を目指して研究を行い、本年度は以下の成果を得た。
1.β2-mアミロイド線維の試験管内形成において、生体に存在する線維形成促進因子として親水基に陰性荷電を持つ界面活性剤である、リゾフォスファチジン酸とリゾフォスファチジルエタノールアミンなどのリゾリン脂質が線維伸長促進効果、核形成誘起効果、形成された線維の安定化効果を有することを報告した。透析患者の体内でのリゾリン脂質の効果を解析し、血中濃度の上昇を確認したが、他の促進因子と相乗的に作用している可能性、あるいは関節などの沈着局所で高濃度となり作用している可能性がある。また、類似する促進因子である遊離脂肪酸(オレイン酸等)についても、患者血液中の濃度測定などを行い、透析患者における生理的線維形成促進機構を探索した。
2.脳アミロイドアンギオパチーを引きおこす脳血管へのβアミロイド線維沈着について、核形成過程に影響を及ぼす生体分子間相互作用の解析を行った。この為にチオフラビンT分光蛍光法とプレートリーダー型分光蛍光光度計を用いたハイスループット反応・解析系を構築した。次いで、この反応系に各種生体分子(細胞外マトリックス成分、グリコサミノグリカン等)を添加し、核形成の促進・抑制効果の解析を行った。

Report

(2 results)
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (30 results)

All 2008 2007 2006 Other

All Journal Article (25 results) (of which Peer Reviewed: 8 results) Presentation (5 results)

  • [Journal Article] Procollagen C-proteinase enhancer-1 (PCPE-1) interacts with β_2-microglobulin (β2-m) and may help initiate β2-m amyloid fibril formation in connective tissues2008

    • Author(s)
      Morimoto, H., et. al.
    • Journal Title

      Matrix Biol. 27

      Pages: 211-219

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Thiol compounds inhibit the formation of amyloid fibrils by β_2-microglobulin at neutral pH2008

    • Author(s)
      Yamamoto, K., et. al.
    • Journal Title

      J. Mol. Biol. 376

      Pages: 258-268

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Amyloid nucleation triggered by agitation of β_2-microglobulinunder acidic and neutral pH conditions2008

    • Author(s)
      Sasahara, K., et. al.
    • Journal Title

      Biochemistry 47

      Pages: 2650-2660

    • Related Report
      2007 Annual Research Report
    • 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

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cross-seeding and cross-competition in mouse apolipoprotein A-II amyloid fibrils and protein A amyloid fibrils2007

    • Author(s)
      Yan, J., et. al.
    • Journal Title

      Am. J. Pathol. 171

      Pages: 172-180

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heat-induced conversion of β_2-microglobulin and hen egg-white lysozyme into amyloid fibrils2007

    • Author(s)
      Sasahara, K., et. al.
    • Journal Title

      J. Mol. Biol. 372

      Pages: 981-991

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Visualization and Classification of Amyloid β Supramolecular Assemblies2007

    • Author(s)
      Yagi, H., et. al.
    • Journal Title

      Biochemistry 46

      Pages: 15009-15017

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 透析アミロイドーシス-基礎研究から治療戦略Update-2007

    • Author(s)
      内木 宏延, 他
    • Journal Title

      透析会誌 40

      Pages: 1025-1025

    • Related Report
      2007 Annual Research Report
  • [Journal Article] β_2-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

    • Related Report
      2007 Annual Research Report
  • [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

    • Related Report
      2007 Annual Research Report
  • [Journal Article] Inhibitors of amyloid β-protein aggregation mediated by GM1-containing raft-like membranes.2007

    • Author(s)
      Matsuzaki, K. et al.
    • Journal Title

      Biochim. Biophys. Acta 1768(1)

      Pages: 122-130

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Cerebrospinal fluid of Alzheimer's disease and dementia with Lewy bodies patients enhances α-synuclein fibril formation in vitro.2007

    • Author(s)
      Ono, K.et al.
    • Journal Title

      Exp. Neurol. 203(2)

      Pages: 579-583

    • Related Report
      2006 Annual Research Report
  • [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(7)

      Pages: 1888-1899

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Flow-induced alignment of amyloid protofilaments revealed by linear dichroism.2007

    • Author(s)
      Adachi, R. et al.
    • Journal Title

      J. Biol. Chem. 282(12)

      Pages: 8978-8983

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Heat-triggered conversion of protofibrils into mature amyloid fibrils of β_2-microglobulin.2007

    • Author(s)
      Sasahara, K. et al.
    • Journal Title

      Biochemistry 46(11)

      Pages: 3286-3293

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Anti-amyloidogenic effects of antioxidants : Implications for the prevention and therapeutics of Alzheimer's disease.2006

    • Author(s)
      Ono, K.et al.
    • Journal Title

      Biochim. Biophys. Acta 1762(6)

      Pages: 575-586

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Seeding-dependent propagation and maturation of β_2-microglobulin amyloid fibrils under high pressure.2006

    • Author(s)
      Chatani, E. et al.
    • Journal Title

      J. Mol. Biol. 359(4)

      Pages: 1086-1096

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Exothermic effects observed upon heating of β_2-microglobulin monomers in the presence of amyloid seeds.2006

    • Author(s)
      Sasahara, K. et al.
    • Journal Title

      Biochemistry 45(29)

      Pages: 8760-8769

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Conformation of amyloid fibrils of β_2-microglobulin probed by tryptophan mutagenesis.2006

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

      J. Biol. Chem. 281(41)

      Pages: 31061-31069

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Mechanism by which the amyloid-like fibrils of a β_2-microglobulin fragment are induced by fluorine-substituted alcohols.2006

    • Author(s)
      Yamaguchi, KI. et al.
    • Journal Title

      J. Mol. Biol 363(1)

      Pages: 279-288

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Blood-borne factors inhibit Alzheimer's β-amyloid fibril formation in vitro.2006

    • Author(s)
      Ono, K.et al.
    • Journal Title

      Exp. Neurol. 202(1)

      Pages: 125-132

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Real-time and single fibril observation of the formation of amyloid β spherulitic structures.2006

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

      J. Biol. Chem. 281(44)

      Pages: 33677-33683

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 3D structure of amyloid protofilaments of β_2-microglobulin fragment probed by solid-state NMR.2006

    • Author(s)
      Iwata, K. et al.
    • Journal Title

      Proc. Natl. Acad. Sci. U. S. A. 103(48)

      Pages: 18119-18124

    • Related Report
      2006 Annual Research Report
  • [Journal Article] The development of preventives and therapeutics for Alzheimer's disease that inhibit the formation of β-amyloid fibrils (fAβ), as well as destabilize preformed fAβ.2006

    • Author(s)
      Ono, K.et al.
    • Journal Title

      Curr. Pharm. Des. 12(33)

      Pages: 4357-4375

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Lysophospholipids Induce the Nucleation and Extension of β_2-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] Uniforming the molecular weight of amyloid fibrils by ultrasonication2007

    • Author(s)
      茶谷 絵理, 他
    • Organizer
      日本生物物理学会第45回年会
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-23
    • Related Report
      2007 Annual Research Report
  • [Presentation] The effects of reductant on the amyloid fibril formation of β2-microglobulin2007

    • Author(s)
      山本 香織, 他
    • Organizer
      日本生物物理学会第45回年会
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-23
    • Related Report
      2007 Annual Research Report
  • [Presentation] Packing density of amyloid-like and amyloid fibrils2007

    • Author(s)
      李 映昊, 他
    • Organizer
      日本生物物理学会第45回年会
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-23
    • Related Report
      2007 Annual Research Report
  • [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] 透析アミロイド症病態解明へのアプローチupdate2007

    • Author(s)
      山本 卓, 他
    • Organizer
      第52回日本透析医学会学術集会・総会
    • Place of Presentation
      大阪市
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2018-03-28  

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