Development of antibodies and aggregation inhibitors for amyloid β peptides based on the new aggregation model

2008 Fiscal Year Final Research Report

• Project/Area Number: 18208011
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Bioproduction chemistry/Bioorganic chemistry
• Research Institution: Kyoto University
• Principal Investigator: IRIE Kazuhiro Kyoto University, 大学院・農学研究科, 教授 (00168535)
• Co-Investigator(Kenkyū-buntansha): TAKEGOSHI Kiyonori 京都大学, 大学院・理学研究科, 教授 (10206964) ; SHIMIZU Takahiko 地方独立行政法人東京都健康長寿医療センター, 東京都健康長寿医療センター研究所, 研究員 (40301791)
• Project Period (FY): 2006 – 2008
• Keywords: アルツハイマー病 / βアミロイド / 凝集 / 固体NMR / β-シート / Aβ抗体 / ESR

Research Abstract

アルツハイマー病の原因物質である42残基のアミロイドβタンパク(Aβ42)の凝集体中に存在する複数のコンホマーのうち，22, 23番目及び38, 39番目の2箇所にターン構造を有する「毒性コンホマー」が，ラジカル化を介した神経細胞毒性発現において重要であることを明らかにした．本結果に基づき，毒性コンホマーを特異的に認識・排除する抗体の作成を試みるとともに，Aβ42の凝集を阻害する化合物を広く天然に求め，ポリフェノールの一種であるタキシフォリンに顕著な活性を認めた．

Research Products

• [Journal Article] Identification of physiological and toxic conformations in Aβ42 aggregates (2009)
  • Author(s): Y. Masuda, 他3名, 2-4番目, K. Takegoshi, T. Shimizu, T. Shirasawa, *K. Irie
  • Journal Title: ChemBioChem 10 Pages: 287-295
  • Peer Reviewed
• [Journal Article] βアミロイドの毒性コンホメーション (2008)
  • Author(s): *入江一浩, 増田裕一
  • Journal Title: 化学と生物 46 Pages: 431-434
  • Peer Reviewed
• [Journal Article] Verification of the intermolecular parallel β-sheet in E22K-Aβ42 aggregates by solid-state NMR using rotational resonance : implications for the supramolecular arrangement of the toxic conformer of Aβ42 (2008)
  • Author(s): Y. Masuda, 他2名, 2-3番目, K. Takegoshi, T. Shimizu, T. Shirasawa, *K. Irie
  • Journal Title: Biosci. Biotechnol. Biochem. 72 Pages: 2170-2175
  • Peer Reviewed
• [Journal Article] アミロイドβ (Aβ42) の毒性コンホメーションの提唱 (2008)
  • Author(s): *村上一馬, 清水孝彦, 白澤卓二, 入江一浩
  • Journal Title: 基礎老化研究 32 Pages: 25-29
  • Peer Reviewed
• [Journal Article] Isomerization and/or racemization at Asp23 of Aβ42 do not increase its aggregative ability, neurotoxicity, and radical productivity in vitro (2008)
  • Author(s): K. Murakami, M. Uno, Y. Masuda, T. Shimizu, T. Shirasawa, *K. Irie,
  • Journal Title: Biochem. Biophys. Res. Commun. 366 Pages: 745-751
  • Peer Reviewed
• [Journal Article] Verification of the C-terminal intramolecular β-sheet in Aβ42 aggregates using solid-state NMR (2008)
  • Author(s): Y. Masuda, 他3名, 2-4番目, K. Takegoshi, T. Shimizu, T. Shirasawa, *K. Irie
  • Journal Title: Bioorg. Med. Chem. Lett. 18 Pages: 3206-3210
  • Peer Reviewed
• [Journal Article] Distance measurement between Tyr-10 and Met-35 in amyloid β by site-directed spin labeling ESR : implications for the stronger neurotoxicity of Aβ42 than Aβ40 (2007)
  • Author(s): K. Murakami, H. Hara, Y. Masuda, H. Ohigashi, *K. Irie
  • Journal Title: ChemBioChem 8 Pages: 2308-2314
  • Peer Reviewed
• [Journal Article] The toxic conformation of the 42-residue amyloid β peptide and its relevance to oxidative stress in Alzheimer's disease (2007)
  • Author(s): *K. Irie., K. Murakami, 他5名, 3-7番目, K. Takeoshi, H. Fukuda, M. Nagao, T. Shimizu, T. Shirasawa
  • Journal Title: Mini-Rev. Med. Chem. 7 Pages: 1001-1008
  • Peer Reviewed
• [Presentation] 固体NMR及びESRによるβアミロイドの立体構造と神経細胞毒性発現機構の解析 (2008)
  • Author(s): 入江一浩
  • Organizer: 理研シンポジウム「第9回分析・解析技術と化学の最先端」
  • Place of Presentation: 埼玉
  • Year and Date: 2008-12-09
• [Presentation] Verification of the intermolecular parallel β-sheet in E22K-Aβ42 (Italian) aggregates by solid-state NMR using rotational resonance (2008)
  • Author(s): Kazuhiro Irie
  • Organizer: 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Washington D.C., USA
  • Year and Date: 2008-11-16
• [Presentation] βアミロイドの立体構造解析と神経細胞毒性発現機構 (2008)
  • Author(s): 入江一浩
  • Organizer: 第43回天然物化学談話会
  • Place of Presentation: 大阪
  • Year and Date: 2008-07-12
• [Presentation] アルツハイマー病因ペプチドの毒性コンホメーション (2008)
  • Author(s): 入江一浩
  • Organizer: 2008年度日本農芸化学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-03-29
• [Presentation] Toxic conformer of the 42-mer amyloid β (Aβ42) (2007)
  • Author(s): Kazuhiro Irie
  • Organizer: 37th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2007-11-06
• [Presentation] 固体NMRならびにESRによるアミロイドβ (Aβ42) の毒性コンホメーションの解析 (2007)
  • Author(s): 入江一浩
  • Organizer: 第49回天然有機化合物討論会
  • Place of Presentation: 札幌
  • Year and Date: 2007-09-19
• [Presentation] アルツハイマー病因ペプチド (Aβ42) の神経細胞毒性発現機構 (2007)
  • Author(s): 入江一浩
  • Organizer: 東北薬科大学ハイテクリサーチセンター第2回シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2007-05-25
• [Presentation] Malignant conformation of the 42-mer amyloid β peptide (2006)
  • Author(s): Kazuhiro Irie
  • Organizer: 2nd International Symposium on Biomolecules and Related Compounds
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2006-11-10
• [Presentation] Formation and stabilization mechanism of the β-amyloid radical (2006)
  • Author(s): Kazuma Murakami
  • Organizer: ICOB-5 & ISCNP-25 IUPAC International Conference on Biodiversity and Natural Products
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2006-07-24
• [Book] Identification of toxic conformation in Aβ42 aggregates using solid-state NMR (2009)
  • Author(s): Y. Masuda, 他3名, K. Takegoshi, *K. Irie
  • Total Pages: 25-28
  • Publisher: The Japanese Peptide Society
• [Book] 'Malignant' conformation of Alzheimer's β peptide (Aβ42) through radical formation (H. Ishida and H. Mihara (Eds.)) (2006)
  • Author(s): K. Murakami, *K. Irie, 他3名, T. Shimizu, T. Shirasawa
  • Total Pages: 19-20
  • Publisher: The Japanese Peptide Society
• [Remarks] ホームページ等
  • URL: http://www.orgchem.kais.kyoto-u.ac.jp/
• [Patent(Industrial Property Rights)] βアミロイド, 及びそれを用いたアルツハイマー病治療薬又は予防薬のスクリーニング方法 (2005)
  • Inventor(s): 入江一浩, 村上一馬, 大東肇, 永尾雅哉, 白澤卓二, 清水孝彦
  • Industrial Property Rights Holder: 入江一浩, 村上一馬, 大東肇, 永尾雅哉, 白澤卓二, 清水孝彦
  • Patent Publication Number: 公開特許公報 (A), 特開2006-265189 (P2006-265189A)
  • Filing Date: 2005-03-24