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

• 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
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000); Fiscal Year 2008: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2007: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2006: ¥24,960,000 (Direct Cost: ¥19,200,000、Indirect Cost: ¥5,760,000)
• 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 / アルツハイマ-病 / β-シ-ト / アルツハイマー / Aβ42 / R2 / βシート / シリマリン / タキシフォリン / DARR / スピンラベル

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] Identification of Physiological and Toxic Conformations in Aβ42 Aggregates (2009)
  • Author(s): Y. Masuda,(他3名) K. Takegoshi, T. Shimizu, T. Shirasawa, K. Irie
  • Journal Title: ChemBioChem 10 Pages: 287-295
  • Peer Reviewed
• [Journal Article] Identification of physiological and toxic conformations in Abeta42 aggregates (2009)
  • Author(s): Yuichi Masuda
  • Journal Title: Chem Bio Chem 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
  • NAID: 10024333845
  • 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
  • NAID: 10027531218
  • 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
  • NAID: 10024377833
  • 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] βアミロイドの毒性コンポメ-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 13-sheet in E22K-Aβ42 Aggregates by Solid-state NMR Using Rotational Resonance : Implications for the Supramolecular Arrangement of the Toxic Conformer of Aβ42. Biosci. (2008)
  • Author(s): Y. Masuda,(他3名),K. Takegoshi, T. Shimizu, T. Shirasawa, K. Irie
  • Journal Title: Biotechnol. Biochem 72 Pages: 2170-2175
  • Peer Reviewed
• [Journal Article] Verification of the C-terminal intramolecular beta-sheet in Abeta42 aggregates using solid-state NMR : implications for potent neurotoxicity through the fonnation of radicals (2008)
  • Author(s): Yuichi Masuda
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 18 Pages: 3206-3210
  • Peer Reviewed
• [Journal Article] Verification of the intermolecular parallel beta-sheet in E22K-Abeta42 aggregates by solid-state NMR using rotational resonance : implications for the supramolecular arrangement of the toxic conformer of Abeta42 (2008)
  • Author(s): Yuichi Masuda
  • Journal Title: Bioscience, Biotechnology & Biochemistry 72 Pages: 2170-2175
  • Peer Reviewed
• [Journal Article] βアミロイドの毒性コンホメーシヨン (2008)
  • Author(s): 入江一浩
  • Journal Title: 化学と生物 46 Pages: 431-434
  • Peer Reviewed
• [Journal Article] アミロイドβ(A β42)の毒性コンホメーシヨンの提唱 (2008)
  • Author(s): 村上一馬
  • Journal Title: 基礎老化研究 32 Pages: 25-29
  • Peer Reviewed
• [Journal Article] Isomerization and/or racemization at Asp-23 of Aβ42 do not increase its aggregative ability and neurotoxicity in vitro (2008)
  • Author(s): Kazuma Murakami
  • Journal Title: Biochemical and Biophysical Research Communications 366 Pages: 745-751
  • 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
• [Journal Article] Distance Measurement between Tyr-10 and Met-35 in Amyloid (3 by Site-directed Spin Labeling ESR : Implications for the Stronger Neurotoxicity of Aβ342 than Aβ340 (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) K. Takegoshi, H. Fukuda, M. Nagao, T. Shimizu, T. Shirasawa
  • Journal Title: Mini-Rev. Med. Chem 7 Pages: 1001-1008
  • 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): Kazuhiro Irie
  • Journal Title: Mini-Reviews in Medicinal Chemistry 7 Pages: 1001-1008
  • 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): Kazuma Murakami
  • Journal Title: Chem Bio Chem 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): Kazuhiro Irie
  • Journal Title: Mini-Reviews in Medicinal Chemistry (in press)
• [Journal Article] Malignant' conformation of Alzheimer's β peptides (Aβ42) through radical formation (2006)
  • Author(s): Kazuma Murakami
  • Journal Title: Peptide Science 2006 (H. Ishida and H. Mihara Eds.) Pages: 19-20
• [Presentation] アミロイドβのAsp23における異性化あるいはラセミ化か凝集能および神経細胞毒性に及ぼす影響 (2009)
  • Author(s): 村上一馬
  • Organizer: 2009年度日本農芸化学会大会
  • Place of Presentation: 博多
  • Year and Date: 2009-03-28
• [Presentation] 酸化型タキシフォリンのアミロイドβ凝集阻害活性 (2009)
  • Author(s): 宇野真弓
  • Organizer: 2009年度日本農芸化学会大会
  • Place of Presentation: 博多
  • Year and Date: 2009-03-28
• [Presentation] Aβ42凝集体のC末端における分子内β-シート構造の固体NMRによる検証 (2009)
  • Author(s): 増田裕一
  • Organizer: 2009年度日本農芸化学会大会
  • Place of Presentation: 博多
  • Year and Date: 2009-03-28
• [Presentation] Glu-22欠損アミロイドβのラジカル産生能とオリゴマー形成能の充進 (2009)
  • Author(s): 鈴木啓之
  • Organizer: 2009年度日本農芸化学会大会
  • Place of Presentation: 博多
  • Year and Date: 2009-03-28
• [Presentation] アミロイドβタンパクの毒性コンホメーション (2008)
  • Author(s): 入江一浩
  • Organizer: 第54回白鷺セミナー
  • Place of Presentation: 大阪
  • Year and Date: 2008-12-15
• [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] 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: 東京
  • 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] 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] Verification of the intermolecular parallel beta-sheet in E22K-Abeta42 (Italian) aggregates by solid-state NMR using rotational resonance : implications for the supramolecular arrangement of the toxic conformer of Abeta42 (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] Verification of the C-terminal lntramolecular antiparallel beta-sheet in Abeta42 aggregates using solid-state NMR : implications for potent neurotoxicity through thefo rmation of radicals (2008)
  • Author(s): Yuichi Masuda
  • Organizer: 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Washington D. C., USA
  • Year and Date: 2008-11-16
• [Presentation] Isomerization and/or racemization at Asp23 of Abeta42 do not enhance its aggregation, neurotoxicity, and radical productivity in vitro (2008)
  • Author(s): Kazuma Murakami
  • Organizer: 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Washington D. C., USA
  • Year and Date: 2008-11-16
• [Presentation] βアミロイドの毒性コンホメーションの同定 (2008)
  • Author(s): 増田裕一
  • Organizer: 第45回プチド討論会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-29
• [Presentation] βアミロイドの毒性コンホメーシヨンのESRならびに固体NMRによる検証 (2008)
  • Author(s): 入江一浩
  • Organizer: 第27回日本認知症学会集会
  • Place of Presentation: 前橋
  • Year and Date: 2008-10-10
• [Presentation] βアミロイド凝集体に存在する音陛コンホメーシヨンの同定 (2008)
  • Author(s): 増田裕一
  • Organizer: 第27回日本認知症学会集会
  • Place of Presentation: 前橋
  • Year and Date: 2008-10-10
• [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] βアミロイド心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] βアミロイド凝集体のC末端における分子内βシート構造の固体NMRによる検証 (2008)
  • Author(s): 増田裕一
  • Organizer: 第43回天然物化学談話会
  • Place of Presentation: 大阪
  • Year and Date: 2008-07-11
• [Presentation] アミロイドβ(Aβ42)の病的コンホメーシヨンの提唱 (2008)
  • Author(s): 村上一馬
  • Organizer: 日本基礎老化学会第31回大会
  • Place of Presentation: 松本
  • Year and Date: 2008-06-13
• [Presentation] アミロイドβ凝集体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: 彩都バイオヒルズクラブ プロテオミクスシンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2008-04-28
• [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] アルッハイマ-病因ペプチドの毒性コンポメ-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] アルツハイマー病因ペプチド(Aβ42)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] イタリアン変異βアミロイド凝集体の分子間β-sheet構造の固体NMRによる解析 (2008)
  • Author(s): 増田 裕一
  • Organizer: 2008年度日本農芸化学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-03-28
• [Presentation] シリマリンに含まれるフラボノイド類のβアミロイド凝集阻害活性 (2008)
  • Author(s): 宇野 真弓
  • Organizer: 2008年度日本農芸化学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-03-28
• [Presentation] アミロイドβペプチドのターン構造形成とアスパラギン酸残基修飾 (2007)
  • Author(s): 清水 孝彦
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [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] Analysis of a turn structure in the 42-mer β-amyloid aggregates using solid-state NMR (2007)
  • Author(s): Yuichi Masuda
  • Organizer: 37th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2007-11-06
• [Presentation] Distance analysis between Tyr-10 and Met-35 in amyloid β using site-directed spin labeling ESR: implications for the stronger neurotoxicity of Aβ42 than Aβ40 (2007)
  • Author(s): Kazuma Murakami
  • 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] 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] 固体NMRを用いたアミロイドβ凝集体の立体構造解析 (2007)
  • Author(s): 中西 梓
  • Organizer: 第46回NMR討論会
  • Place of Presentation: 札幌
  • Year and Date: 2007-09-11
• [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] 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: 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
  • 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
  • Publisher: The Japanese Peptide Society
• [Remarks] ホームページ等
  • URL: http://www.orgchem.kais.kyoto-u.ac.jp/
• [Remarks]
  • URL: http://www.orgchem.kais.kyoto-u.ac.jp/
• [Remarks]
  • 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: 2006-265189
  • Filing Date: 2005-03-24
• [Patent(Industrial Property Rights)] βアミロイド,及びそれを用いたアルツハイマ-病治療薬又は予防薬のスクリ-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: 2006-265189
  • Filing Date: 2005-03-24