Molecular mechanisms of the aberrant metabolism of tryptophan in Alzheimer's disease

• Project/Area Number: 21590353
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• 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, ラジオアイソトープ管理室, 室長 (70163342)
• Co-Investigator(Kenkyū-buntansha): KAGAWA Syota 独立行政法人国立長寿医療研究センター, ラジオアイソトープ管理室, 研究員 (30463201)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: アルツハイマー病 / トリプトファン / IFN-γ / ミクログリア / アミロイドβペプチド

Research Abstract

Alzheimer's disease(AD) is an increasing neurodegenerative disease with growing elderly population. Prevention and treatment of AD is an urgent social issue. In this study, molecular mechanisms of the aberrant metabolism of tryptophan via induction of indoleamine 2, 3-dioxygnase in AD, which leads to a generation of neurotoxin quinolinic acid, was studied. In particular, the putative receptor for amyloid. peptide expressed in activated macrophages infiltrating into amyloid plaques was tried to be characterized.

Research Products

• [Journal Article] Novel candesartan derivatives as indoleamine 2, 3-dioxygenase inhibitors (2012)
  • Author(s): Matsuno K, Yamazaki H, Isaka Y, takai K, Unno Y, Ogo N, Ishikawa Y, Fujii S, Takikawa O, Asai A
  • Journal Title: Med. Chem. Comm. Volume: 3 Issue: 4 Pages: 475-479
  • DOI: 10.1039/c2md00278g
  • Peer Reviewed
• [Journal Article] Identification of novel kynurenine production-inhibiting benzenesulfonamide derivatives in cancer cells (2012)
  • Author(s): Nakano S, Takai K, Isaka Y, Takahashi S, Unno Y, Ogo N, Matsuno K, Takikawa O, Asai A.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 419 Issue: 3 Pages: 556-561
  • DOI: 10.1016/j.bbrc.2012.02.059
  • Peer Reviewed
• [Journal Article] Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy (2012)
  • Author(s): Wang, D.
  • Journal Title: Int J Oncol Volume: 40 Issue: 4 Pages: 929-34
  • DOI: 10.3892/ijo.2011.1295
  • Peer Reviewed
• [Journal Article] Vascular endothelial expression of indoleamine 2, 3-dioxygenase 1 forms a positive gradient towards the feto-maternal interface (2011)
  • Author(s): Blaschitz A, Gauster M, Fuchs D, Lang I, Maschke P, Ulrich D, Karpf E, Takikawa O, Schimek MG, Dohr G, Sedlmayr P
  • Journal Title: PLoS ONE Volume: 6 Issue: 7 Pages: e21774-e21774
  • DOI: 10.1371/journal.pone.0021774
  • Peer Reviewed
• [Journal Article] Interferon-γregulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2, 3 dioxygenase(IDO) (2011)
  • Author(s): Croitoru-Lamoury J, Lamoury FM, Caristo M, Suzuki K, Walker D, Takikawa O, Taylor R, Brew BJ
  • Journal Title: PLoS One Volume: 16 ; 6(2) Issue: 2 Pages: e14698-e14698
  • DOI: 10.1371/journal.pone.0014698
  • Peer Reviewed
• [Journal Article] Indoleamine 2, 3-dioxygenase promotes peritoneal dissemination of ovarian cancer through inhibition of natural killercell function and angiogenesis promotion (2011)
  • Author(s): Nonaka H, Saga Y, Fujiwara H, Akimoto H, Yamada A, Kagawa S, Takei Y, Machida S, Takikawa O, Suzuki M.
  • Journal Title: Int J Oncol Volume: 38 Issue: 1 Pages: 113-120
  • DOI: 10.3892/ijo_00000830
  • Peer Reviewed
• [Journal Article] Interferon-γ regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase(IDO). (2011)
  • Author(s): Croitoru-Lamoury J, Lamoury FM, Caristo M, Suzuki K, Walker D, Takikawa O, Taylor R, Brew BJ.
  • Journal Title: PLoS One. Volume: 6 Pages: 14698-14698
  • Peer Reviewed
• [Journal Article] Indoleamine 2,3-dioxygenase promotes peritoneal dissemination of ovarian cancer through inhibition of natural killer cell function and angiogenesis promotion. (2011)
  • Author(s): Nonaka H, Saga Y, Fujiwara H, Akimoto H, Yamada A, Kagawa S, Takei Y, Machida S, Takikawa O, Suzuki M.
  • Journal Title: Int J Oncol. Volume: 38 Pages: 113-120
  • Peer Reviewed
• [Journal Article] S-benzylisothiourea derivatives as small-molecule inhibitors of indoleamine-2, 3-dioxygenase (2010)
  • Author(s): Matsuno K, Takai K, Isaka Y, Unno Y, Sato M, Takikawa O, Asai A
  • Journal Title: Bioorg Med Chem Lett Volume: 20 Issue: 17 Pages: 5126-5129
  • DOI: 10.1016/j.bmcl.2010.07.025
  • Peer Reviewed
• [Journal Article] Indoleamine 2, 3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy (2010)
  • Author(s): Inaba T, Ino K, Kajiyama H, Shibata K, Yamamoto E, Kondo S, Umezu T, Nawa A, Takikawa O, Kikkawa F
  • Journal Title: Gynecol Oncol Volume: 117 Issue: 3 Pages: 423-428
  • DOI: 10.1016/j.ygyno.2010.02.028
  • Peer Reviewed
• [Journal Article] S-benzylisothiourea derivatives as small-molecule inhibitors of indoleamine-2,3-dioxygenase. (2010)
  • Author(s): Matsuno K, Takai K, Isaka Y, Unno Y, Sato M, Takikawa O, Asai A.
  • Journal Title: Bioorg Med Chem Lett. Volume: 20 Pages: 5126-5129
  • Peer Reviewed
• [Journal Article] Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy. (2010)
  • Author(s): Inaba T, Ino K, Kajiyama H, Shibata K, Yamamoto E, Kondo S, Umezu T, Nawa A, Takikawa O, Kikkawa F.
  • Journal Title: Gynecol Oncol Volume: 117 Pages: 423-428
  • Peer Reviewed
• [Journal Article] Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes : functional involvement of the CTLA-4/B7 and CCL22/CCR4 interactions (2009)
  • Author(s): Onodera T, Jang MH, Guo Z, Yamasaki M, Hirata T, Bai Z, Tsuji NM, Nagakubo D, Yoshie O, Sakaguchi S, Takikawa O, Miyasaka M
  • Journal Title: J Immunol Volume: 183 Issue: 9 Pages: 5608-5614
  • DOI: 10.4049/jimmunol.0804116
  • Peer Reviewed
• [Journal Article] Hemoglobin induces the expression of indoleamine 2, 3-dioxygenase in dendritic cells through the activation of PI3K, PKC, and NF-kappaB and the generation of reactive oxygen species (2009)
  • Author(s): Ogasawara N, Oguro T, Sakabe T, Matsushima M, Takikawa O, Isobe K, Nagase F
  • Journal Title: J Cell Biochem Volume: 108 Issue: 3 Pages: 716-725
  • DOI: 10.1002/jcb.22308
  • Peer Reviewed
• [Journal Article] Role of the immunosuppressive enzyme indoleamine 2, 3-dioxygenase in the progression of ovarian carcinoma (2009)
  • Author(s): Inaba T, Ino K, Kajiyama H, Yamamoto E, Shibata K, Nawa A, Nagasaka T, Akimoto H, Takikawa O, Kikkawa F
  • Journal Title: Gynecol Oncol Volume: 115 Issue: 2 Pages: 185-192
  • DOI: 10.1016/j.ygyno.2009.07.015
  • Peer Reviewed
• [Journal Article] Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+Foxp3+T regulatory cells (2009)
  • Author(s): Brenk M, Scheler M, Koch S, Neumann J, Takikawa O, Hacker G, Bieber T, von Bubnoff D
  • Journal Title: J Immunol Volume: 183 Issue: 1 Pages: 145-154
  • DOI: 10.4049/jimmunol.0803277
  • Peer Reviewed
• [Journal Article] Proinflammatory cytokine interferon-gamma increases induction of indoleamine 2, 3-dioxygenase in monocytic cells primed with amyloid beta peptide 1-42 : implications for the pathogenesis of Alzheimer's disease (2009)
  • Author(s): Yamada A, Akimoto H, Kagawa S, Guillemin GJ, Takikawa O.
  • Journal Title: J Neurochem Volume: 110 Issue: 3 Pages: 791-800
  • DOI: 10.1111/j.1471-4159.2009.06175.x
  • Peer Reviewed
• [Journal Article] Free iron ions decrease indoleamine 2, 3-dioxygenase expression and reduce IFNgamma-induced inhibition of Chlamydia trachomatis infection (2009)
  • Author(s): Krausse-Opatz B, Wittkop U, Gutzki FM, Schmidt C, Jurgens-Saathoff B, Meier S, Beckmann B, Takikawa O, Morgan MA, Tsikas D, Stichtenoth DO, Wagner AD, Zeidler H, Kohler L
  • Journal Title: Microb Pathog Volume: 46 Issue: 6 Pages: 289-297
  • DOI: 10.1016/j.micpath.2009.03.001
  • Peer Reviewed
• [Journal Article] Proinflammatory cytokine interferon-gamma increases induction of indoleamine 2,3-dioxygenase in monocytic cells primed with amyloid beta peptide 1-42 : implications for the pathogenesis of Alzheimer's disease (2009)
  • Author(s): Yamada A, Akimoto H, Kagawa S, Guillemin GJ, Takikawa O.
  • Journal Title: J Neurochem. 110 Pages: 791-800
  • Peer Reviewed
• [Presentation] アルツハイマー病モデルAPP/Tauマウスの脳組織における脂質メタボローム解析 (2012)
  • Author(s): 田島陽子、前川京子、村山真由子、石川将己、徳江繭子、最上(西巻)知子、中西広樹、池田和貴、有田誠、田口良、キョウ建生、奥野海良人、新飯田俊平、滝川修、斉藤嘉朗
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-30
• [Presentation] アルツハイマー病モデルAPP/Tauマウスにおける血漿の脂質メタボローム解析 (2012)
  • Author(s): 石川将己、前川京子、田島陽子、村山真由子、徳江繭子、最上(西巻)知子、中西広樹、池田和貴、有田誠、田口良、キョウ建生、奥野海良人、新飯田俊平、滝川修、斉藤嘉朗
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-30
• [Presentation] CE/MSメタボロミクスによるアルツハイマー病の尿、血液及び脳バイオマーカーの検出 (2011)
  • Author(s): 滝川修、新飯田俊平、曽我朋義
  • Organizer: 第6回メタボロームシンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2011-10-13
• [Presentation] 内在性神経毒キノリン酸による海馬アミロイドβペプチドの増加機構:神経細胞ではなく反応アストロサイトに因る (2011)
  • Author(s): 滝川修、奥野海良人、張桂琴、横井寛、吉見立也、三河隆太
  • Organizer: 第84回日本生化学大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-23
• [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 (2011)
  • Author(s): 吉見立也、張桂琴、奥野海良人、横井寛、三河隆太、滝川修
  • Organizer: 第84回日本生化学大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-22
• [Presentation] アルツハイマー病根本治療薬の開発を目指して (2011)
  • Author(s): 滝川修
  • Organizer: 第47回シグナル伝達医学グローバルCOE学術講演会
  • Place of Presentation: 神戸
  • Year and Date: 2011-08-12
• [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 (2011)
  • Author(s): 張桂琴、奥野海良人、横井寛、吉見立也、滝川修
  • Organizer: 日本基礎老化学会第34回大会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-16
• [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 (2011)
  • Author(s): 奥野海良人、張桂琴、吉見立也、三河隆太、高柳亜紀子、滝川修
  • Organizer: 第33回日本トリプトファン研究会
  • Place of Presentation: 船橋
• [Presentation] 内因性神経毒キノリン酸で誘導される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 (2011)
  • Author(s): 張桂琴、奥野海良人、吉見立也、三河隆太、高柳亜紀子、滝川修
  • Organizer: 第33回日本トリプトファン研究会
  • Place of Presentation: 船橋
• [Presentation] Development of prophylaxis and therapy for vascular dementia by anti-E-selectin antibody using the mouse model (2011)
  • Author(s): Adachi K, Kunimoto S, Takeda K, Ohtani T, Watanabe A, Takikawa O, Maruyama W, Wakita H
  • Organizer: The Asia-Pacific Interdisciplinary Research Conference 2011
  • Place of Presentation: Toyohashi
• [Presentation] Astrocytes but not neurons are responsible for the hippocampal increase of amyloidβpeptide induced by neurotoxin quinolinic acid (2011)
  • Author(s): Okuno A, Zhang G, Yokoi H, Takikawa O
  • Organizer: AAIC 2011
  • Place of Presentation: Paris, France
• [Presentation] Detection of urine, blood, and brain biomarkers for Alzheimer's disease by capillary electrophoresis/mass spectrometry(CE-MS)-based metabolomic analysis (2011)
  • Author(s): Takikawa O, Niida S, Soga T.
  • Organizer: Seventh International Conference of the Metabolomics Society
  • Place of Presentation: Cairns, Australia
• [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 (2011)
  • Author(s): 滝川修、奥野海良人、張桂琴、横井寛、吉見立也
  • Organizer: 日本基礎老化学会第34回大会
  • Place of Presentation: 東京
• [Presentation] キノリン酸によるアミロイドβペプチドの増加機構-神経細胞ではなく反応性アストロサイトに因る (2011)
  • Author(s): 奥野海良人、張桂琴、横井寛、吉見立也、滝川修
  • Organizer: 日本基礎老化学会第34回大会
  • Place of Presentation: 東京
• [Presentation] Endogenous neurotoxin quinolinic acid may play a primary role in the pathology of Alzheimer's disease by killing neurons and increasing the amyloid beta peptide levels in the hippocampus (2011)
  • Author(s): Takikawa O, Kagawa S, Okuno A, Yokoi H, Zhang Q
  • Organizer: AD/PD2011(アルツハイマー病・パーキンソン病2011)
  • Place of Presentation: バルセロナ(スペイン)
• [Presentation] Detection of urine, blood, and brain biomarkers for Alzheimer's disease by capillary electrophoresis/mass spectrometry (CE-MS)-based metabolomic analysis (2011)
  • Author(s): Takikawa O, Niida S, Soga T
  • Organizer: Seventh International Conference of the Metabolomics Society
  • Place of Presentation: Cairns, Australia
• [Presentation] Astrocytes but not neurons are responsible for the hippocampal increase of amyloid ss peptide induced by neurotoxin quinolinic acid (2011)
  • Author(s): Okuno A, Zhang G, Yokoi H, Takikawa O
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Paris, France
• [Presentation] Development of prophylaxis and therapy for vascular dementia by anti-E-selectin antibody using the mouse model (2011)
  • Author(s): Adachi K, Kunimoto S, Takeda K, Ohtani T, Watanabe A, Takikawa O, Maruyama W, Wakita H
  • Organizer: The Asia-Pacific Interdisciplinary Research Conference 2011
  • Place of Presentation: 豊橋
• [Presentation] アルツハイマー病で見られるトリプトファン代謝異常の病態生理学的意義:神経毒キノリン酸のダークパワー (2010)
  • Author(s): 滝川修
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Assay development and screening for new chemical entities as IDO Inhibitors (2010)
  • Author(s): Takai K, Isaka Y, Unno Y, Matsuno K, Sato M, Takikawa O, Asai A
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] アルツハイマー病で見られるトリプトファン代謝異常の病態生理学的意義 : 神経毒キノリン酸のダークパワー (2010)
  • Author(s): 滝川修
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Assay development and screening for new chemical entities as IDO inhibitors (2010)
  • Author(s): K Takai, Y Isaka, Y Unno, K Matsuno, M Sato, O Takikawa, A Asai
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] 内在性神経毒キノリン酸によるアミロイドβペプチド増加機構とその病態生理学的意義 (2010)
  • Author(s): 奥野海良人、香川正太、横井寛、張桂琴、滝川修
  • Organizer: 第32回日本トリプトファン研究会学術集会
  • Place of Presentation: 彦根
  • Year and Date: 2010-12-05
• [Presentation] LPSの抹消投与による脳内炎症モデルの作製:アルツハイマー病の理解を目指して (2010)
  • Author(s): 横井寛、奥野海良人、張桂琴、滝川修
  • Organizer: 第32回日本トリプトファン研究会学術集会
  • Place of Presentation: 彦根
  • Year and Date: 2010-12-05
• [Presentation] IDO阻害活性を有するS-benzylisothiourea誘導体の構造活性相関 (2010)
  • Author(s): 松野研司、高井一成、井坂吉伸、海野雄加、佐藤雅之、滝川修、浅井章良
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-17
• [Presentation] IDO阻害活性を有するS-benzylisothiourea誘導体の構造活性相関 (2010)
  • Author(s): 山崎寛史、松野研司、高井一成、井坂吉伸、海野雄加、佐藤雅之、浅井章良、滝川修
  • Organizer: 第25回農薬デザイン研究会
  • Place of Presentation: 浜松
  • Year and Date: 2010-11-05
• [Presentation] Endogenous neurotoxin quinolinic acid may play a primary role in the pathology of Alzheimer's disease by increasing the amyloid beta peptide levels (2010)
  • Author(s): Takikawa O, Kagawa S, Okuno A, Yokoi H, Zhang Q
  • Organizer: ICAD2010(国際アルツハイマー病学会2010)
  • Place of Presentation: ホノルル(米国)
  • Year and Date: 2010-07-05
• [Presentation] Endogenous neurotoxin quinolinic acid may play a primary role in the pathology of Alzheimer's disease by increasing the amyloid beta peptide levels (2010)
  • Author(s): Takikawa O
  • Organizer: ICNCC 2010(第1回国際神経組織培養研究会)
  • Place of Presentation: ソウル(韓国)
  • Year and Date: 2010-06-25
• [Presentation] アルツハイマー病とトリプトファン代謝異常:神経毒キノリン酸による神経細胞死とアミロイドβペプチド増加 (2010)
  • Author(s): 滝川修、香川正太、張桂琴、横井寛
  • Organizer: 日本基礎老化学会第33回大会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-06-18
• [Presentation] Neurotoxin quinolinic acid produced in overactivated microglia may contribute to the progression of Alzheimer's disease (2009)
  • Author(s): Kagawa S, Yamada A, Akimoto H, Yokoi H, Guillemin GJ, Takikawa O
  • Organizer: 第12回国際トリプトファン研究会
  • Place of Presentation: フローレンス(イタリア)
  • Year and Date: 2009-07-10
• [Presentation] Neurotoxin quinolinic acid produced in overactivated microglia may contribute to the progression of Alzheimer's disease. (2009)
  • Author(s): Kagawa S, Yamada A, Akimoto H, Yokoi H, Guillemin GJ, Takikawa O
  • Organizer: 第12回国際トリプトファン研究会
  • Place of Presentation: フローレンス(イタリア)
  • Year and Date: 2009-07-10
• [Remarks]
  • URL: http://www.ncgg.go.jp/department/lrs/index-lrs-j.htm
• [Patent(Industrial Property Rights)] アルツハイマー病の診断マーカー、アルツハイマー病の予防及び治療薬のスクリーニング方法並びにアルツハイマー病の診断方法 (2010)
  • Inventor(s): 滝川修、曽我朋義
  • Industrial Property Rights Holder: 財団法人ヒューマンサイエンス財団
  • Filing Date: 2010-05-17
• [Patent(Industrial Property Rights)] アルツハイマー病の診断マーカー、アルツハイマー病の予防及び治療薬のスクリーニング方法並びにアルツハイマー病の診断方法 (2010)
  • Inventor(s): 滝川修曽我朋義
  • Industrial Property Rights Holder: 財団法人ヒューマンサイエンス財団
  • Industrial Property Number: 2010-113496
  • Filing Date: 2010-05-17
• [Patent(Industrial Property Rights)] ベンゾイミダゾール誘導体を有効成分とするIDO阻害剤 (2009)
  • Inventor(s): 滝川修、浅井章良、松野研司、海野雄加
  • Industrial Property Rights Holder: 独立行政法人国立長寿医療研究センター・ファルマIP
  • Industrial Property Number: 2009-133633
  • Filing Date: 2009-06-03
• [Patent(Industrial Property Rights)] 含硫化合物を有効成分として含有するIDO阻害剤 (2009)
  • Inventor(s): 滝川修、浅井章良、松野研司、海野雄加
  • Industrial Property Rights Holder: 独立行政法人国立長寿医療研究センター・ファルマIP
  • Industrial Property Number: 2009-205484
  • Filing Date: 2009-09-07