Analysis of neurodegenerative mechanisms based on the development of beta amyloid oligomer-selective proteases
Project/Area Number |
19K15694
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 37010:Bio-related chemistry
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Research Institution | Tokyo University of Agriculture and Technology |
Principal Investigator |
Tsukakoshi Kaori 東京農工大学, 工学(系)研究科(研究院), 助教 (20708474)
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Project Period (FY) |
2019-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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Keywords | アミロイドβ / アルツハイマー病 / プロテアーゼ / プリオンタンパク質 / オリゴマー |
Outline of Research at the Start |
アルツハイマー病の発症にはアミロイドβの凝集体の一種・アミロイドβオリゴマーが関与するとされている。アミロイドβオリゴマーは神経細胞内外の様々な部位に局在すると報告されているが、どの部位のアミロイドβオリゴマーが神経変性の原因であるかは不明である。そこで本研究ではアミロイドβオリゴマーを選択的に分解するプロテアーゼを開発し、これを用いて部位ごとにアミロイドβオリゴマーが与える神経変性機構を解析する。
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Outline of Final Research Achievements |
In this research project, a protease with amyloid-β (Aβ) oligomer selectivity, a drug target for Alzheimer's disease, was developed. Neprilysin was selected as the protease to degrade Aβ oligomer. As a result, recombinant production of Aβ oligomer-binding peptide-fused neprilysin with retained enzyme activity was successfully achieved. It was also found that the multivalency effect is important for the binding of peptides to Aβ oligomers. Future analysis of cells and tissues in which local Aβ oligomers are lowered by proteolysis is expected to reveal the action that triggers cell death.
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Academic Significance and Societal Importance of the Research Achievements |
Aβオリゴマーを標的とした二つの抗体医薬が上市され、認知機能低下を抑制する薬効が報告されている。しかし、今なおAβオリゴマーがどのように神経細胞を障害するのか、そのメカニズムは明らかでない。本研究課題の成果を基盤としそのメカニズムを解明することができれば、新しい創薬ターゲットの発見や高価な抗体医薬に変わる新薬の開発につながると期待できるため、その学術的・社会的意義は大きい。
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Report
(5 results)
Research Products
(56 results)
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[Journal Article] Effects of G-Quadruplex Ligands on the Topology, Stability, and Immunostimulatory Properties of G-Quadruplex-Based CpG Oligodeoxynucleotides2022
Author(s)
Anh Thi Tram Tu, Kazuaki Hoshi, Yue Ma, Taiji Oyama, Satoko Suzuki, Kaori Tsukakoshi, Kazuo Nagasawa, Kazunori Ikebukuro, Tomohiko Yamazaki
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Journal Title
ACS Chem Biol
Volume: 17 (7)
Issue: 7
Pages: 1703-1713
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Enhancement of the Immunostimulatory Effect of Phosphodiester CpG Oligodeoxynucleotides by an Antiparal-lel Guanine-Quadruplex Structural Scaffold.2021
Author(s)
Safitri, F., Tu, A., Hoshi, K., Shobo, M., Zhao, D., Witarto, A., Sumarsono, S., Giri-Rachman, E., Tsukakoshi, K., Ikebukuro, K., and Yamazaki, T.
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Journal Title
Sensors (Basel)
Volume: 11(11)
Issue: 11
Pages: 1617-1617
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] G-quadruplex-forming aptamer enhances the peroxidase activity of myoglobin against luminol.2021
Author(s)
*Tsukakoshi, K., *Yamagishi, Y. (*co-first author), Kanazashi, M., Nakama, K., Oshikawa, D., Savory, N., Matsugami, A., Hayashi, F., Lee, J., Saito, T., Sode, K., Khunathai, K., Kuno, H. & Ikebukuro, K.
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Journal Title
Nucleic Acids Res
Volume: 49
Issue: 11
Pages: 6069-6081
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Specific detection of a therapeutic antibody using an anti-idiotype DNA aptamer and drastic improvement of its affinity by pH optimization2021
Author(s)
Yutaka Shimizu, Lisa Moriya, Taro Saito, Kaori Tsukakoshi, Koichi Abe, Jinhee Lee, Kinuko Ueno, Ryutaro Asano, Brian V. Jones, Tomohiro Yamada, Tatsuki Nakano, Jiaxing Tong, Asami Hishiki, Kodai Hara, Hiroshi Hashimoto, Koji Sode, Toshimasa Toyo’oka, Kenichiro Todoroki, and Kazunori Ikebukuro
Organizer
BIOSENSORS 2021
Related Report
Int'l Joint Research
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[Presentation] Aptameric enzyme subunit enhances the peroxidase activity of myoglobin against luminol2021
Author(s)
Kaori Tsukakoshi,Yasuko Yamagishi, Mana Kanazashi, Kenta Nakama, Daiki Oshikawa, Nasa Savory, Akimasa Matsugami, Fumiaki Hayashi, Jinhee Lee, Taiki Saito, Koji Sode, Kanjana Khunathai, Hitoshi Kuno, Kazunori Ikebukuro
Organizer
ISNAC2021
Related Report
Int'l Joint Research
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[Presentation] Improvement in binding property of the anti-idiotype aptamer against bevacizumab based on structural information2019
Author(s)
Yutaka Shimizu, Kaori Tsukakoshi, Ryutaro Asano, Tatsuki Nakano, Jiaxing Tong, Asami Hishiki, Kodai Hara, Hiroshi Hashimoto, Toshimasa Toyo’oka, Kenichiro Todoroki, Kazunori Ikebukuro
Organizer
ISNAC2019
Related Report
Int'l Joint Research
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