The mechanisms of quinolinic acid-induced infiltration of reactive astrocytes and the amyloid beta peptide production in the activated glial cells

• Project/Area Number: 24590397
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: National Center for Geriatrics and Gerontology
• Principal Investigator: TAKIKAWA Osamu 独立行政法人国立長寿医療研究センター, 治療薬探索研究部, 室長 (70163342)
• Co-Investigator(Kenkyū-buntansha): OKUNO Alato 独立行政法人国立長寿医療研究センター, 長寿医療研究センター・ラジオアイソトープ管理室, 特任研究員 (50623980)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アルツハイマー病 / トリプトファン代謝 / アミロイドβペプチド / キノリン酸 / 神経毒 / IDO / ＩＤＯ

Outline of Final Research Achievements

Alzheimer's disease (AD) is an increasing neurodegenerative disease and prevention and treatment of AD is an urgent social issue. Amyloid β peptide (Aβ) deposition is a well-known pathological feature in AD brains. A neurotoxin quinolinic acid (QA) has recently been to be involved in the AD pathology. In this study, the putative mediators responsible for QA-induced infiltration of reactive astrocytes in the AD brains have been tried to be identified and the molecular mechanism of the high Aβ production in reactive astrocytes was clarified.

Research Products

• [Journal Article] Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment. (2014)
  • Author(s): Tanizaki Y(1), Kobayashi A, Toujima S, Shiro M, Mizoguchi M, Mabuchi Y, Yagi S, Minami S, Takikawa O, Ino K.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 8 Pages: 966-73
  • DOI: 10.1111/cas.12445
  • Peer Reviewed / Open Access
• [Journal Article] トリプトファン代謝異常の病態生理学的意義：がんとアルツハイマー病を中心として (2014)
  • Author(s): 滝川 修
  • Journal Title: アミノ酸研究 Volume: 8 Pages: 25-34
• [Journal Article] Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer's disease. (2013)
  • Author(s): Tajima Y, Ishikawa M, Maekawa K, Murayama M, Senoo Y, Nishimaki-Mogami T, Nakanishi H, Ikeda K, Arita M, Taguchi R, Okuno A, Mikawa R, Niida S, Takikawa O, Saito Y.
  • Journal Title: Lipids Health Dis Volume: 12 Issue: 1 Pages: 68-68
  • DOI: 10.1186/1476-511x-12-68
  • Peer Reviewed
• [Journal Article] Synthesis and biological evaluation of novel tryptoline derivatives as indoleamine 2, 3- dioxygenase (IDO) inhibitors. (2013)
  • Author(s): Tanaka, Minoru; Li, Xin; Hikawa, Hidemasa; Suzuki, Takafumi; Tsutsumi, Katsuhiko; Sato, Masashi; Takikawa, Osamu; Suzuki, Hideharu; Yokoyama, Yuusaku,
  • Journal Title: Bioorganic & Medicinal Chemistry (2013), 21(5), 1159-1165. Volume: 21(5) Issue: 5 Pages: 1159-1165
  • DOI: 10.1016/j.bmc.2012.12.028
  • Peer Reviewed
• [Journal Article] NMR-based metabolomics of urine in a mouse model of Alzheimer’s disease: identification of oxidative stress biomarkers (2013)
  • Author(s): Fukuhara, K., Ohno, A., Ota, Y., Senoo, Y., Maekawa, K., Okuda, H., Kurihara, M., Okuno, A., Niida, S., Saito, Y., Takikawa, O
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 52 Issue: 2 Pages: 133-138
  • DOI: 10.3164/jcbn.12-118
  • NAID: 130004466706
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection. (2013)
  • Author(s): Higashitani K, Kanto T, Kuroda S, Yoshio S, Matsubara T, Kakita N, Oze T, Miyazaki M, Sakakibara M, Hiramatsu N, Mita E, Imai Y, Kasahara A, Okuno A, Takikawa O, Hayashi N, Takehara T.
  • Journal Title: J Gastroenterol.[Epub ahead of print] Volume: 未定
  • NAID: 10031177017
  • Peer Reviewed
• [Journal Article] Downregulation of indoleamine-2,3-dioxygenase in cervical cancer cells suppresses tumor growth by promoting natural killer cell accumulation. (2012)
  • Author(s): Sato, N.
  • Journal Title: Oncol Rep. Volume: 28 Issue: 5 Pages: 1574-1578
  • DOI: 10.3892/or.2012.1984
  • Peer Reviewed
• [Presentation] Development of High-speed and Super Sensitive Device for Detection of Amyloid-β Peptide Using an Ion Image Sensor. (2014)
  • Author(s): Okuno A, Yoshimi T, Okumura K, Sawada K, Takikawa O.
  • Organizer: IEEE International Symposium on Micro-NanoMechatronics and Human Science(MHS) 2014
  • Place of Presentation: Nagoya,Japan.
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] イメージング質量分析の最前線：創薬と生命科学への応用 (2014)
  • Author(s): 滝川修、吉見立也
  • Organizer: 第87回生化学会大会フォーラム4F04
  • Place of Presentation: 京都
  • Year and Date: 2014-10-18
• [Presentation] ヒト血清中のアミロイドβ分解活性の同定 (2014)
  • Author(s): 三河隆太、奥野海良人、高柳亜紀子、吉見立也、滝川修
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-18
• [Presentation] New modulator of the tumoural immuno escape via Indoleamin 2,3-dioxygenase (IDO) inhibition. (2014)
  • Author(s): Antonio Coluccia, Giuseppe La Regina, Okuno A, Takikawa O, Romano Silvestri.
  • Organizer: XXV CONGRESSO NAZIONALE DELLA SCI “SCI2014”
  • Place of Presentation: Rend CS, Italy.
  • Year and Date: 2014-09-07
• [Presentation] Characterization of Amyloid-β Degrading Activity in Human Serum. (2014)
  • Author(s): Mikawa R, Okuno A, Takayanagi A, Okada K, Yoshimi T, Takikawa O.
  • Organizer: 日本基礎老化学会第37回大会
  • Place of Presentation: 東浦
  • Year and Date: 2014-06-26
• [Presentation] Blood biomarkers for Alzheimer’s disease revealed by capillary electrophoresis/mass spectrometry (CE/MS)-based metabolomics. (2014)
  • Author(s): Kayano M, Hirayama A, Washimi Y, Bundo M, Sakurai T, Tokuda H, Soga T, Niida S, Takikawa O.
  • Organizer: Tenth Annual International Conference of the Metabolomics Society
  • Place of Presentation: Tsuruoka, Japan.
  • Year and Date: 2014-06-25
• [Presentation] 経管栄養施行中の重症心身障害児(者)の栄養障害と免疫機能 -インドールアミン酸素添加酵素(IDO)との関連について- (2013)
  • Author(s): 大森啓充、滝川修、眞山義民、奥野海良人、山﨑雅美、福場浩正、村田芳夫、松本信夫、品川友江、宮地隆史、住元了、鈴木修一、 宮野前健、児玉浩子
  • Organizer: 第35回日本臨床栄養学会
  • Place of Presentation: 京都
• [Presentation] NMRを用いたアルツハイマー病モデルマウスのメタボローム解析 (2012)
  • Author(s): 福原 潔、大野彰子、太田庸介、前川京子、奥田晴宏、栗原正明、奥野海良人、新飯田俊平、斎藤嘉朗、滝川 修
  • Organizer: 第65回日本酸化ストレス学会
  • Place of Presentation: 徳島
• [Presentation] 新規IDO阻害剤の活性評価 (2012)
  • Author(s): 李シン(昕）、田中実、滝川修、横山祐作
  • Organizer: 第40回構造活性相関シンポジウム
  • Place of Presentation: 岡崎
• [Presentation] 血管内皮細胞におけるAβ産生機構と脳アミロイド血管症
  • Author(s): 三河隆太、吉見立也、奥野海良人、岡田健、高柳亜紀子、滝川修
  • Organizer: 第36回日本基礎老化学会
  • Place of Presentation: 大阪
• [Presentation] 反応性アストロサイトによるAβ産生：アルツハイマー病のアミロイド代謝異常に関する新知見
  • Author(s): 滝川修
  • Organizer: Neuro2013
  • Place of Presentation: 京都
• [Presentation] 脳血管細胞によるAβ産生と脳アミロイド血管症
  • Author(s): 三河隆太、奥野海良人、岡田健、高柳亜紀子、吉見立也、滝川修
  • Organizer: 第35回神経組織培養研究会
  • Place of Presentation: 大阪
• [Presentation] Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer’s disease.
  • Author(s): Tajima Y, Maekawa Keiko, Ishikawa M, Murayama M, Senoo Y, Nishimaki-Mogami T, Nakanishi H, Kazutaka I, Arita M, Taguchi R, Okuno A, Mikawa R, Niida S, Takikawa O, Saito Y.
  • Organizer: The 9th Annual Conference of the Metabolomics Society
  • Place of Presentation: Glasgow, Scotland
• [Presentation] Implications of brain microvessel endothelial cell-derived amyloid β peptide in cerebral amyloid angiopathy associated with Alzheimer’s disease.
  • Author(s): Takikawa O, Mikawa R, Okuno A, Yoshimi T, Okada K, Takayanagi A.
  • Organizer: Alzheimer’s disease Association International Conference (AAIC) 2013
  • Place of Presentation: Boston, America.
• [Presentation] 血管内皮細胞によるAβ産生調節機構：脳アミロイド血管症におけるその病態生理学的意義
  • Author(s): 三河隆太、吉見立也、奥野海良人、岡田健、高柳亜紀子、滝川修
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] Kinetic and protein-ligand interaction studies of human tryptophan 2,3-dioxygenase, identified the modulation of enzymatic reactions by tryptophan.
  • Author(s): 岡田健、三河隆太、奥野海良人、高柳亜紀子、山岸まゆみ、吉見立也、滝川修
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] ヒトTryptophan 2,3-dioxygenaseのアロステリック効果による酵素反応調節機構
  • Author(s): 岡田健、三河隆太、奥野海良人、吉見立也、滝川修
  • Organizer: 第35回日本トリプトファン研究会
  • Place of Presentation: 京都
• [Presentation] メタボロミクスによるアルツハイマー病早期発見診断マーカーの探索
  • Author(s): 滝川修、新飯田俊平、平山明由、曽我朋義
  • Organizer: 第８回メタボロームシンポジウム
  • Place of Presentation: 福岡
• [Presentation] Benzimidazole構造を有する新規indoleamine 2,3-dioxygenase(IDO)阻害剤の合成と活性評価
  • Author(s): 福田美和、脇稔、浅井章良、滝川修、宮地弘幸、松野研司
  • Organizer: 第31回メディシナルケミストリーシンポジウム
  • Place of Presentation: 広島
• [Presentation] Characterization of Amyloid-βDegrading Activity in Human Serum.
  • Author(s): 三河隆太、吉見立也、奥野海良人、岡田健、高柳亜紀子、滝川修
  • Organizer: 第6回NAGOYAグローバルリトリート
  • Place of Presentation: 東浦
• [Presentation] indoleamine 2,3-dioxygenase (IDO) 阻害活性を有するbenzimidazole系化合物の創製
  • Author(s): 福田美和、脇稔、浅井章良、滝川修、宮地弘幸、松野研司
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
• [Presentation] トリプトファン代謝酵素IDO・TDOと免疫抑制
  • Author(s): 滝川
  • Organizer: 第34回癌免疫外科研究会
  • Place of Presentation: 岡山
  • Invited
• [Presentation] トリプトファン代謝異常と疾患：アルツハイマー病とがん免疫抑制作用
  • Author(s): 滝川修
  • Organizer: 第52回日本栄養・食糧学会近畿支部大会
  • Place of Presentation: 彦根
  • Invited
• [Presentation] トリプトファン代謝異常の病態生理学的意義：アルツハイマー病とがんを中心に
  • Author(s): 滝川修
  • Organizer: 第17回「アミノ酸セミナー：基礎と臨床を結ぶ会」
  • Place of Presentation: 東京
  • Invited
• [Presentation] Aβ Production from Reactive Astrocytes Induced by Endogenous Neurotoxin Quinolinic Acid : A New Aspect of Alzheimer’s Disease.
  • Author(s): Okuno A, Zhang G, Yoshimi T, Mikawa R, Takikawa O.
  • Organizer: Alzheimer’s disease Association International Conference (AAIC) 2012
  • Place of Presentation: Vancouver, Canada
• [Presentation] 血中miRNAとEndothelial Microparticles - microRNAs in the endothelial microparticles-
  • Author(s): 新飯田俊平、山本誠士、村松昌、東英梨月、本山昇、滝川修
  • Organizer: 第４回日本RNAi研究会
  • Place of Presentation: 広島
• [Presentation] Lipidomic analysis of brain and plasma from a mouse model of Alzheimer’s disease.
  • Author(s): Tajima Y, Maekawa K, Ishikawa M, Murayama M, Nishimaki-Mogami T, Nakanishi1 H, Ikeda K, Arita M, Taguchi R, Gong J, Okuno A, Niida S, Takikawa O, Saito Y.
  • Organizer: 第53回国際脂質生化学会
  • Place of Presentation: Banff, Canada
• [Presentation] Biological Evaluation on New Inhibitors of Indoleamine 2, 3-Dioxygenase.
  • Author(s): Li X, Tanaka M, Takikawa O, Yokoyama Y.
  • Organizer: The Ninth China-Japan Joint Symposium on Drug Design and Development
  • Place of Presentation: Guilin, China
• [Presentation] Organ Specificity of Tryptophan Metabolism in Humans.
  • Author(s): Takikawa O.
  • Organizer: 第13回国際トリプトファン研究会サテライトシンポジウム
  • Place of Presentation: Brisbane, Australia
  • Invited
• [Presentation] Pathogenic role of IDO in Alzheimer’s disease: Astrocytes but not neurons are responsible for the increase of amyloid β peptide induced by neurotoxin quinolinic acid.
  • Author(s): Okuno A, Yoshimi T, Okada K, Mikawa R, Takayanagi A, Takikawa O.
  • Organizer: 第13回国際トリプトファン研究会
  • Place of Presentation: Sydney, Australia
• [Presentation] アルツハイマー病モデルマウスの脳組織及び血漿における脂質メタボローム解析
  • Author(s): 田島陽子、前川京子、石川将己、村山真由子、妹尾勇弥、最上(西巻)知子、中西広樹、池田和貴、有田誠、田口良、檜垣小百合、奥野海良人、新飯田俊平、滝川修、斎藤嘉朗
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] 反応性アストロサイトによるアミロイドβペプチド産生機構
  • Author(s): 吉見立也、奥野海良人、岡田健、三河隆太、高柳亜紀子、滝川修
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] The pathological role of IDO-medicated tryptophan metabolism in Alzheimer’s disease.
  • Author(s): Takikawa O
  • Organizer: 旭川医科大学 第1回教育研究センター主催国際シンポジウム：トリプトファン代謝と脳機能/疾患
  • Place of Presentation: 旭川
  • Invited
• [Remarks] 国立長寿医療研究センター 認知症先進医療開発センター 治療薬探索研究部/リード分子探索研究室
  • URL: http://www.ncgg.go.jp/department/tsr/lds/index.html
• [Remarks] 国立長寿医療研究センター 研究所 ラジオアイソトープ管理室
  • URL: http://www.ncgg.go.jp/department/lrs/index.html
• [Remarks] 国立長寿医療研究センター 認知症先進医療開発センター 治療薬探索研究部/リード分子探索研究室
  • URL: http://www.ncgg.go.jp/department/tsr/lds/index.html
• [Remarks] 国立長寿医療研究センター 研究所 ラジオアイソトープ管理室
  • URL: http://www.ncgg.go.jp/department/lrs/index.html
• [Patent(Industrial Property Rights)] 化学・物理現象検出方法及びその装置 (2014)
  • Inventor(s): 滝川修、奥野海良人、吉見立也、澤田和明、奥村弘一
  • Industrial Property Rights Holder: 滝川修、奥野海良人、吉見立也、澤田和明、奥村弘一
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-05-28
  • Overseas
• [Patent(Industrial Property Rights)] 微小生体組織片の作製装置、作製方法、及び化合物のスクリーニング方法 (2014)
  • Inventor(s): 滝川修、吉見立也、田中耕一、川畑慎一郎
  • Industrial Property Rights Holder: 滝川修、吉見立也、田中耕一、川畑慎一郎
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-212627
  • Filing Date: 2014-10-17
• [Patent(Industrial Property Rights)] 化学・物理現象検出方法及びその装置 (2013)
  • Inventor(s): 滝川修、奥野海良人、吉見立也、澤田和明、奥村弘一
  • Industrial Property Rights Holder: 滝川修、奥野海良人、吉見立也、澤田和明、奥村弘一
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-05-29
• [Patent(Industrial Property Rights)] アルツハイマー病の発症を予測する方法 (2012)
  • Inventor(s): 滝川修・奥野海良人・その他５名
  • Industrial Property Rights Holder: 滝川修・奥野海良人・その他５名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-151620
  • Filing Date: 2012-07-05