ケミカルシフトの違いを利用したフッ素MR画像による複数の脳内異常蛋白の同時解析

• Project Area: Brain Environment
• Project/Area Number: 26111709
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Shiga University of Medical Science
• Principal Investigator: 遠山 育夫 滋賀医科大学, 分子神経科学研究センター, 教授 (20207533)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 脳神経疾患 / アルツハイマー病 / 核磁気共鳴画像 / 診断 / 治療 / ベータアミロイド / 神経科学

Outline of Annual Research Achievements

本研究では、クルクミンの構造を一部変えた新規の化合物を多種類合成して、アルツハイマー病の老人斑を検出する MR 画像診断用試薬の開発に取り組んできた。今回、それら化合物のひとつである Shiga-Y5 が、認知症の治療効果を持つことをアルツハイマー病のモデルマウスを用いて明らかにした。Shiga-Y5は、アルツハイマー病の画像診断薬としても治療薬としても役立つ可能性を示唆している.。この成果を国際学術誌に掲載・発表した（Neurobiol Aging 36: 201-210 2015)。また、本研究で開発した40種類のクルクミン誘導体のアミロイド結合能や細胞毒性抑制作用などをまとめてデータベース化し、論文発表した（ Biochem Biophys Report 4: 357-368, 2015）。
さらに、フッ素MR画像法を用いると非放射性同位元素である19FのもつNMR信号を利用して、PETと同様な機能画像を得ることができることから、「脳内環境」で開発した技術やMR画像診断薬について総説としてまとめて報告した。なかでも試薬の出す19F-NMR信号のケミカルシフトの違いを利用した二重フッ素画像法を利用して、世界で初めてアミロイドオリゴマーの候補画像を得ることに成功し、国際学術誌に報告した（Ageing Research Reviews, 2016 doi: 10.1016/j.arr.2015.12.008）。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] マレーシア国民大学(マレーシア)
• [Int'l Joint Research] Banner Sun Health Institute(米国)
• [Int'l Joint Research] ハルピン医科大学(中国)
• [Journal Article] Amyloid imaging using fluorine-19 magnetic resonance imaging (19F-MRI). (2016)
  • Author(s): Tooyama I, Yanagisawa D, Taguchi H, Kato T, Hirao K, Shirai N, Sogabe T, Ibrahim NF, Inubushi T, Morikawa S
  • Journal Title: Ageing Research Reviews Volume: 15 Pages: 1568-1637
  • DOI: 10.1016/j.arr.2015.12.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel curcumin derivatives as potent inhibitors of amyloid ß aggregation. (2015)
  • Author(s): Yanagisawa D, Taguchi H, Morikawa S, Kato T, Hirao K, Shirai N, Tooyama I
  • Journal Title: Biochem Biophys Report Volume: 4 Pages: 357-368
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diagnosis of amyloid-positive mild cognitive impairment using structural magnetic resonance imaging: the worth of multiple regions of interest. (2015)
  • Author(s): Vigers P, Shiino A, Tooyama I
  • Journal Title: Integrative Molecular Medicine Volume: 2 Pages: 205-213
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Alpha1-chimaerin, a Rac1 GTPase-activating protein, is expressed at reduced mRNA levels in the brain of Alzheimer's disease patients. (2015)
  • Author(s): Kato T, Konishi Y, Shimohama S, Beach TG, Akatsu H, Tooyama I
  • Journal Title: Neurosci Lett. Volume: ５９０１ Pages: 19-24
  • DOI: 10.1016/j.neulet.2015.02.013
  • Peer Reviewed / Open Access
• [Journal Article] ynthesis and Tautomerism of Curcumin Derivatives and Related Compounds. (2015)
  • Author(s): Taguchi H, Yanagisawa D, Morikawa S, Hirao K, Shirai N, Tooyama I
  • Journal Title: Australian Journal of Chemistry Volume: 68 Pages: 224-229
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Up-regulation of mitochondrial ferritin by proinflammatory cytokines: Implications for a role in Alzheimer’s disease. (2015)
  • Author(s): Yang H, Guan H, Yang M, Liu Z, Takeuchi S, Yanagisawa D, Vincent SR, Zhao S, Tooyama I
  • Journal Title: Journal of Alzheimer's Disease Volume: 45 Issue: 3 Pages: 797-811
  • DOI: 10.3233/jad-142595
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis and Tautomerism of Curcumin Derivatives and Related Compounds. (2015)
  • Author(s): Taguchi H, Yanagisawa D, Morikawa S, Hirao K, Shirai N, Tooyama I
  • Journal Title: Australian Journal of Chemistry Volume: 68 Pages: 224-229
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Curcumin derivative with substitution at C-4 position, but not curcumin, is effective against amyloid pathology in APP/PSI mice (2014)
  • Author(s): Yanagisawa D, Ibraham NF, Taguchi H, Morikawa S, Hirao K, Shirai N, Sogabe T, Tooyama I
  • Journal Title: Neurobiol Aging Volume: 36 Issue: 1 Pages: 210-210
  • DOI: 10.1016/j.neurobiolaging.2014.07.041
  • Peer Reviewed
• [Journal Article] Inhalable Curcumin: Offering the Potential for Translation to Imaging and Treatment of Alzheimer's Disease. (2014)
  • Author(s): McClure R, Yanagisawa D, Stec D, Koktysh D, Xhillari D, Jaeger R, Chekmenev E, Tooyama I, Gore1 JC, Pham W
  • Journal Title: Journal of Alzheimer's Disease Volume: 144 Issue: 1 Pages: 283-295
  • DOI: 10.3233/jad-140798
  • Peer Reviewed / Open Access
• [Journal Article] フッ素ＭＲ画像法によるアミロイドオリゴマーのin vivo病態解析 (2014)
  • Author(s): 遠山育夫、柳沢大治郎、NOr Faeizah Ibrahim, 田口弘康
  • Journal Title: 遺伝子医学MooK Volume: 26 Pages: 190-194
  • Acknowledgement Compliant
• [Presentation] Styrylbenzoxazole and curcumin derivatives that have preferred features of a fluorine-19 MRI probe for amyloid imaging. (2015)
  • Author(s): Ikuo Tooyama, Daijiro Yanagisawa, Hiroyasu Taguchi, Nor Faeizah Ibrahim, Lina Wati Durani, Hamizah Shahirah Hamezah, Koichi Hirao, Nobuaki Shirai, Takayuki Sogabe, Shigehiro Morikaw
  • Organizer: 国際分子イメージング学会2015
  • Place of Presentation: 米国ホノルル市
  • Year and Date: 2015-09-02
  • Int'l Joint Research
• [Presentation] Effect of novel curcumin derivatives on amyloid aggregation and the cell toxicity. (2015)
  • Author(s): 柳沢大治郎、Nor Faeizah Ibrahim、Lina Wati Durani、Hamizah Shahirah Hamezah、田口弘康、遠山育夫
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸市
  • Year and Date: 2015-07-28
• [Presentation] Effects of Novel Curcumin Derivative with C-4 Substituent on Cognitive Impairment and Amyloid Deposition in Appswe/PS1dE9 Mice (2015)
  • Author(s): Daijiro Yanagisawa, Nor Faeizah Ibrahim, Lina Wati Durani, Hamizah Shahirah Hamezah, Hiroyasu Taguchi, Shigehiro Morikawa, Koichi Hirao, Nobuaki Shirai, and Ikuo Tooyama
  • Organizer: アルツハイマー病協会国際会議(AAIC)2015
  • Place of Presentation: 米国ワシントンDC
  • Year and Date: 2015-07-18
  • Int'l Joint Research
• [Presentation] Targeting Antioxidant Pathways in Neurodegeneration (2015)
  • Author(s): Tooyama I
  • Organizer: 第１回抗酸化物質ｓと細胞変性に関する国際会議
  • Place of Presentation: マレーシア国クアラルンプール市
  • Year and Date: 2015-06-03
  • Int'l Joint Research / Invited
• [Presentation] フッ素MRIを利用したAβオリゴマーの画像化法の開発 (2015)
  • Author(s): 柳沢大治郎、Nor Faeizah Ibrahim、田口弘康、森川茂廣、遠山育夫
  • Organizer: 第10回日本分子イメージング学会総会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-20
• [Presentation] Induction of mitochondrial ferritin by proinflammatory cytokines is mediated via NF-kappaB signaling pathway and involves in neuroprotection in Alzheimer’s disease. (2014)
  • Author(s): H. YANG, H. GUAN, M. YANG, Z. LIU, S. ZHAO, S. TAKEUCHI, D. YANAGISAWA, S. R. VINCENT, I. TOOYAMA
  • Organizer: 北米神経科学会（Neuroscience2014）
  • Place of Presentation: 米国ワシントンDC
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Novel curcumin derivative with C-4 substituent inhibits amyloid pathology in APPswe/PS1dE9 mice. (2014)
  • Author(s): D. YANAGISAWA, H. TAGUCHI, N. IBRAHIM, L. DURANI1, S. MORIKAWA, K. HIRAO, N. SHIRAI, T. SOGABE, I. TOOYAMA
  • Organizer: 北米神経科学会（Neuroscience2014）
  • Place of Presentation: 米国ワシントンDC
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Fluorine-19 MRI probe for detecting amyloid deposition in Alzheimer’s disease (2014)
  • Author(s): Ikuo Tooyama, Daijiro Yanagisawa, Hiroyasu Taguchi, Nor Faeizah Ibrahim, Lina Wati Durani, Shigehiro Morikawa, Akihiko Shiino, Koichi Hirao, Nobuaki Shirai,Takayuki Sogabe
  • Organizer: 第３７回日本神経科学大会(Neuroscience 2014)
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-11 – 2014-09-15
• [Presentation] Effect of novel curcumin derivatives on amyloid pathology in APP/PS1 mice (2014)
  • Author(s): Daijiro Yanagisawa, Nor Faeizah Ibrahim, Lina Wati Durani, Hiroyasu Taguchi, Ikuo Tooyama
  • Organizer: 第３７回日本神経科学大会(Neuroscience 2014)
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-09-11 – 2014-09-15
• [Presentation] A novel 19F MRI probe for detecting amyloid deposition in Alzheimer’s disease. (2014)
  • Author(s): Ikuo Tooyama, Daijiro Yanagisawa, Hiroyasu Taguchi, Nor Faeizah Ibrahim, Lina Wati Durani, Akihiko Shiino, Toshiro Inubushi, Koichi Hirao, Nobuaki Shirai, Takayuki Sogabe, Shigehiro Morikawa
  • Organizer: アルツハイマー病国際学会（AAIC2014）
  • Place of Presentation: デンマークコペンハーゲン市
  • Year and Date: 2014-07-14 – 2014-07-17
• [Presentation] 高磁場MR装置を利用したフッ素MRIアミロイドイメージングのためのstyrylbenzoxazole誘導体の開発 (2014)
  • Author(s): 柳沢大治郎、田口弘康、森川茂廣、椎野顯彦、犬伏俊郎、遠山育夫
  • Organizer: 第9回分子イメージング学会
  • Place of Presentation: 大阪市豊中市
  • Year and Date: 2014-05-22 – 2014-05-23
• [Remarks] 分子神経科学研究センター
  • URL: http://ben.shiga-med.ac.jp/~hqmnran/