Development of medicinal seeds for Alzheimer's disease based on the structural analysis of toxic oligomers of amyloid beta

2013 Fiscal Year Final Research Report

• Project/Area Number: 21248015
• 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 京都大学, (連合)農学研究科(研究院), 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 千葉大学, 大学院・医学系研究科, 客員准教授 (40301791) ; MURAKAMI Kazuma 京都大学, 大学院・農学研究科, 准教授 (80571281)
• Project Period (FY): 2009-04-01 – 2014-03-31
• Keywords: アルツハイマー病 / アミロイドβ / 凝集 / 毒性ターン / 抗体 / フラボノイド / オリゴマー

Research Abstract

Aggregation of the 42-mer amyloid beta peptide (Abeta42) plays a critical role in the pathogenesis of Alzheimer's disease (AD). We have recently identified the toxic turn at Glu-22 and Asp-23 of Abeta42. Based on the toxic turn, we developed a new antibody 11A1 that selectively recognized the toxic trimer as well as the intracellular Abeta which could not be detected by commercially available Abeta antibodies. Therefore, 11A1 might become a diagnostic drug for AD. By contrast, we found that catechol-type flavonoids could specifically suppress Abeta42 aggregation by targeting the Lys-residues.

Research Products

• [Journal Article] Site-specific inhibitory mechanism for amyloid-β42 aggregation by catechol-type flavonoids targeting the Lys-residues (2013)
  • Author(s): Sato, M., Murakami, K., Ikubo, H., Uno, M., Nakagawa, Y., Katayama, S., Akagi, K.-i., Masuda, Y., Takegoshi, K., *Irie, K
  • Journal Title: J.Biol.Chem Volume: 288 Pages: 23212-23224
  • DOI: 10.1074/jbc.M113.464222
  • Peer Reviewed
• [Journal Article] A drug screening platform for Alzheimer's disease with intracellular Aβ oligomers using patient-specific iPSCs (2013)
  • Author(s): Kondo, T., (他24名), Murakami, K., Irie, K., Klein, W. L., Mori, H., Asada, T., Takahashi, R., Iwata, N., Yamanaka, S., Inoue, H
  • Journal Title: Cell Stem Cell Volume: 12 Pages: 487-496
  • DOI: 10.1016/j.stem.2013.01.009
  • Peer Reviewed
• [Journal Article] Structure-activity relationship of (+)-taxifolin isolated from silymarin as an inhibitor of amyloid β aggregation (2013)
  • Author(s): Sato, M., Murakami, K., (他5名), Irie, K
  • Journal Title: Biosci. Biotechnol. Biochem Volume: 77 Pages: 1100-1103
  • DOI: 10.1271/bbb.120925
  • Peer Reviewed
• [Journal Article] Non-toxic conformer of Aβ42 may suppress Aβ42-induced toxicity in rat primary neurons : implications for the novel therapeutic strategy of Alzheimer's disease (2013)
  • Author(s): Izuo, N., Murakami, K., (他3名), Shimizu, T., Akaike, A., Irie, K., Kume, T
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 438 Pages: 1-5
  • DOI: 10.1016/j.bbrc.2013.05.106
  • Peer Reviewed
• [Journal Article] Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease (2013)
  • Author(s): Soejima, N., Ohyagi, Y., (他6名), Murakami, K., Irie, K., (他5名)
  • Journal Title: Curr. Alzheimer Res Volume: 10 Pages: 11-20
  • URL: http://www.eurekaselect.com/106388/article
  • Peer Reviewed
• [Journal Article] Toxicity in rat primary neuron through the cellular oxidative stress induced by the turn formation at positions 22 and 23 of Aβ42 (2012)
  • Author(s): Izuo, N., Kume, T., Sato, M., Murakami, K., Irie, K., Izumi, Y., Akaike, A
  • Journal Title: ACS Chem. Neurosci Volume: 3 Pages: 674-681
  • DOI: 10.1021/cn300033k
  • Peer Reviewed
• [Journal Article] Stimulation of the amyloidogenic pathway by cytoplasmic superoxide radicals in an Alzheimer's disease mouse model (2012)
  • Author(s): Murakami, K., Murata, N., Noda, Y., Irie, K., Shirasawa, T., Shimizu, T
  • Journal Title: Biosci. Biotechnol. Biochem Volume: 76 Pages: 1098-1103
  • DOI: 10.1271/bbb.110934
  • Peer Reviewed
• [Journal Article] Early accumulation of intracellular fibrillar oligomers and late congophilic amyloid angiopathy in mice expressing the Osaka intra-Aβ APP mutation (2012)
  • Author(s): Kulic, L., (他10名), Shimizu, T., Murakami, K., Irie, K., (他4名)
  • Journal Title: Transl. Psychiatry Volume: 2 Pages: e183
  • DOI: 10.1038/tp.2012.109
  • Peer Reviewed
• [Journal Article] Analysis of interaction sites of curcumin with the fibrils of 42-residue amyloid β-protein (Aβ42) using solid-state NMR (2011)
  • Author(s): Masuda, Y., (他4名), Irie, K., (他4名), Takegoshi, K
  • Journal Title: Bioorg. Med. Chem Volume: 19 Pages: 5967-5974
  • DOI: 10.1016/j.bmc.2011.08.052
  • Peer Reviewed
• [Journal Article] SOD1 (cupper/zinc superoxide dismutase) deficiency drives amyloid β protein oligomerization and memory loss in mouse model of Alzheimer's disease (2011)
  • Author(s): Murakami, K., (他8名), Irie, K., Shirasawa, T., Shimizu, T
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 44557-44568
  • DOI: 10.1074/jbc.M111.279208
  • Peer Reviewed
• [Journal Article] E22Δ mutation in amyloid β-protein promotes β-sheet transformation, radical production, and synaptotoxicity, but not neurotoxicity (2010)
  • Author(s): Suzuki, T., Murakami, K., (他7名), Irie, K
  • Journal Title: Int. J. Alzheimers Dis Volume: 431320
  • DOI: 10.4061/2011/431320
  • Peer Reviewed
• [Journal Article] Monoclonal antibody against the turn of the 42-residue amyloid β-protein at positions 22 and 23 (2010)
  • Author(s): Murakami, K., (他8名), Shimizu, T., Irie, K
  • Journal Title: ACS Chem. Neurosci Volume: 1 Pages: 747-756
  • DOI: 10.1021/cn100072e
  • Peer Reviewed
• [Journal Article] Silymarin attenuated the amyloid β plaque burden and improved behavioral abnormalities in an Alzheimer's disease mouse model (2010)
  • Author(s): Murata, N., Murakami, K., Ozawa, Y., Kinoshita, N., Irie, K., Shirasawa, T., Shimizu T
  • Journal Title: Biosci. Biotechnol. Biochem Volume: 74 Pages: 2299-2306
  • DOI: 10.1271/bbb.100524
  • Peer Reviewed
• [Journal Article] The turn formation at positions 22 and 23 in the 42-mer amyloid beta peptide : the emerging role in the pathogenesis of Alzheimer's disease (2010)
  • Author(s): Murakami, K., Masuda, Y., Shirasawa, T., Shimizu, T., Irie, K
  • Journal Title: Geriatr. Gerontol. Int Volume: 10 Pages: S169-179
  • DOI: 10.1111/j.1447-0594.2010.00598.x
  • Peer Reviewed
• [Presentation] Vitamin C and silymarin restores Aβ oligomerization and behavioral abnormality in Alzheimer's pathology (2013)
  • Author(s): Murakami, K., Murata, N., Ozawa, Y., Irie, K., Shirasawa, T., Shimizu, T
  • Organizer: Alzheimer's Association International Conference (AAIC) 2013
  • Place of Presentation: Boston, USA
  • Year and Date: 2013-07-15
• [Presentation] ポリフェノールによるアミロイド β の凝集抑制機構 (2013)
  • Author(s): 入江一浩
  • Organizer: 2013年度日本農芸化学会大会シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2013-03-27
  • Invited
• [Presentation] ポリフェノールによるアミロイドβ の凝集阻害機構 (2012)
  • Author(s): 入江一浩, 村上一馬, 佐藤瑞穂, 井久保遥子, 宇野真弓, 中川 優, 片山寿美枝, 赤木謙一
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: つくば
  • Year and Date: 2012-10-28
• [Presentation] カテコール系フラボノイド類によるアミロイドβ の凝集抑制機構 (2012)
  • Author(s): 村上一馬, 佐藤瑞穂, 井久保遥子, 宇野真弓, 中川 優, 片山寿美枝, 赤木謙一, 増田裕一, 竹腰清乃理, 入江一浩
  • Organizer: 第54回天然有機化合物討論会
  • Place of Presentation: 東京
  • Year and Date: 2012-09-19
• [Presentation] Monoclonal antibody against a toxic conformer of Aβ42 with a turn at E22-D23 (2012)
  • Author(s): Irie, K., Murakami, K., Horikoshi-Sakuraba, Y., Kinoshikta, N., Shirasawa, T., Shimizu, T., Tokuda, T
  • Organizer: Alzheimer's Association International Conference (AAIC) 2012
  • Place of Presentation: Vancouver, British Columbia, Canada
  • Year and Date: 2012-07-15
• [Presentation] E22Δ mutation promotes the formation of toxic conformer in Alzheimer's peptide, Aβ42 (2011)
  • Author(s): Murakami, K., Suzuki, T., Izuo, N., Kume, T., Akaike, A., Nagata, T., Nishizaki, T., Tomiyama, T., Takuma, H., Mori, H., Irie, K
  • Organizer: 27th International Symposium on the Chemistry of Natural Products, 7th International Conference on Biodiversity
  • Place of Presentation: Brisbane, Australia
  • Year and Date: 2011-07-11
• [Presentation] アミロイドβ の毒性ターン構造を認識する抗体の開発 (2011)
  • Author(s): 入江一浩
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-19
  • Invited
• [Presentation] アミロイドβ タンパクの毒性コンホメーションの同定と薬剤開発 (2011)
  • Author(s): 入江一浩
  • Organizer: 香川大学農学部第2回公開シンポジウム 「生命を化学の視点から探究する」
  • Place of Presentation: 香川大学農学部
  • Year and Date: 2011-03-14
  • Invited
• [Presentation] Structural analysis of toxic conformer of 42-mer amyloid β peptide using ESR spectrometry (2010)
  • Author(s): Murakami, K. and Irie, K
  • Organizer: Asia-Pacific EPR/ESR symposium
  • Place of Presentation: Jeju, Republic of Korea
  • Year and Date: 2010-10-12
• [Presentation] アミロイドβ (Aβ42) の毒性コンホマー特異的抗体の作製 (2010)
  • Author(s): 村上一馬, 堀越(櫻庭)優子, 村田 央, 野田義博, 増田裕一, 木下憲明, 初田裕幸, 村山繁雄, 白澤卓二, 清水孝彦, 入江一浩
  • Organizer: 第52回天然有機化合物討論会
  • Place of Presentation: 静岡
  • Year and Date: 2010-09-30
• [Presentation] アミロイドβ の毒性コンホマーを標的とした立体構造特異的抗体 (2010)
  • Author(s): 村上一馬, 堀越(櫻庭)優子, 村田 央, 野田義博, 増田裕一, 木下憲明, 初田裕幸, 村山繁雄, 白澤卓二, 清水孝彦, 入江一浩
  • Organizer: 2010年度日本農芸化学会大会
  • Place of Presentation: 東京
  • Year and Date: 2010-03-29
• [Book] 固体NMR およびESR によるアミロイド β の立体構造解析と毒性ターン構造特異抗体の開発, 遺伝子医学MOOK21 号「最新ペプチド合成技術とその創薬研究への応用」 (2012)
  • Author(s): 村上一馬, 増田裕一, *入江一浩
  • Total Pages: 211-216
  • Publisher: メディカルドゥ
• [Remarks]
  • URL: http://www.orgchem.kais.kyoto-u.ac.jp/
• [Patent(Industrial Property Rights)] アミロイド β のターン構造を認識する抗体 (2011)
  • Inventor(s): 入江一浩, 村上一馬, 増田裕一, 清水孝彦,白 澤卓二, 清藤 勉
  • Industrial Property Rights Holder: 入江一浩, 村上一馬, 増田裕一, 清水孝彦,白 澤卓二, 清藤 勉
  • Industrial Property Rights Type: 公開特許公報 (A)
  • Industrial Property Number: WO 2011/045945 A1
  • Filing Date: 2011-04-21
  • Overseas