Analysis of neurodegenerative mechanisms based on the development of beta amyloid oligomer-selective proteases

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K15694
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 37010:Bio-related chemistry
• 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)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: アミロイドβ / アルツハイマー病 / プロテアーゼ

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.

Free Research Field

生物工学

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。