アミロイド線維形成の重合核依存性重合モデルと線維形成阻害薬の探索

• 内木 宏延

  福井大学医学部医学科病因病態医学講座分子病理学領域

• 長谷川 一浩

  福井大学医学部医学科病因病態医学講座分子病理学領域

• 小野 賢二郎

  金沢大学大学院医学系研究科脳老化・神経病態学（神経内科学）

• 山田 正仁

  金沢大学大学院医学系研究科脳老化・神経病態学（神経内科学）

書誌事項

タイトル別名

• A Search for Antiamyloidogenic Compounds Based on a Nucleation-Dependent Polymerization Model
• アミロイド センイ ケイセイ ノ ジュウゴウカク イソンセイ ジュウゴウ モデル ト センイ ケイセイ ソガイヤク ノ タンサク

抄録

  We have proposed that a nucleation-dependent polymerization model could explain the general mechanisms of amyloid fibril formation in vitro. Based on this model, we systematically demonstrated that several classes of organic compounds (e.g., wine-related polyphenols, non-steroidal anti-inflammatory drugs) not only inhibit the formation of Aβ amyloid fibrils from Aβ and their extension, but also destabilize Aβ amyloid fibrils dose-dependently in vitro. We found significant positive correlations of the effective concentrations (EC₅₀) of these compounds ranging from 10 nM to 10 μM, for the formation and destabilization of Aβ amyloid fibrils. We next investigated the anti-amyloidogenic effects of five flavonoids on Aβ amyloid fibrils in vitro. Oxidized flavonoids generally inhibited fibril formation significantly more potently than fresh compounds. By surface plasmon resonance (SPR) analysis, distinct association and dissociation reactions of myricetin (Myr) to Aβ amyloid fibrils were observed, in contrast to the very weak binding to the Aβ monomer. A significant decrease in the rate of fibril extension was observed when>0.5 μM of Myr was injected into the SPR experimental system. These findings suggest that flavonoids, especially Myr exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fibrils, rather than to Aβ monomers. This working model should prove useful not only for the rational development of preventives and therapeutics for Alzheimer's disease and other human amyloidosis, but also for understanding the basic mode of action of amyloid imaging compounds.<br>

収録刊行物

• 薬学雑誌

  薬学雑誌 130 (4), 503-509, 2010

  公益社団法人 日本薬学会

キーワード

• amyloid fibril
• antiamyloidogenic compound
• nucleation-dependent polymerization model

詳細情報

• CRID: 1390001206129371136
• NII論文ID: 130000259538
• NII書誌ID: AN00284903
• DOI: 10.1248/yakushi.130.503
• ISSN: 13475231
• ISSN: 00316903
• NDL書誌ID: 10650385
• Web Site: http://hdl.handle.net/2297/28399
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I10650385
• Web Site: http://www.jstage.jst.go.jp/article/yakushi/130/4/130_4_503/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2010265306
• 本文言語コード: ja
• データソース種別:
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• 抄録ライセンスフラグ: 使用不可