Analysis of the mechanism of amyloid-beta toxicity using model peptides which displays metal ion-dependent aggregate formation.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16362
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Setsunan University
• Principal Investigator: Taniguchi Masanari 摂南大学, 薬学部, 助教 (50710696)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: アルツハイマー病 / アミロイドβ / 金属イオン

Outline of Final Research Achievements

Amyloid-β (Aβ) accumulation and aggregation are important factors in the pathogenesis of Alzheimer's disease (AD), and several studies have shown that metal ions such as Cu2+ and Zn2+ play important roles in the formation and stabilization of neurotoxic Aβ aggregates, but the molecular mechanisms of Aβ cytotoxicity Aβ cytotoxicity has not yet been fully elucidated. We have previously shown that the amyloid peptide Aβ1-29 undergoes a conformational change in the presence of Cu2+ and exhibits neurotoxicity. In the present study, we performed CD spectroscopic analysis using peptides in which the His residue, which is important for Aβ1-29 to bind Cu2+, was modified to an Ala residue, and found that there is a secondary structure common to amyloid peptides that show toxicity against neurons. Furthermore, human islet amyloid polypeptide (hIAPP, Amylin), which is associated with the development of diabetes mellitus, may exhibit neurotoxicity by adopting a similar secondary structure.

Free Research Field

分析化学

Academic Significance and Societal Importance of the Research Achievements

Aβと金属イオンに関する研究は全世界で精力的に行われているが、in vitro研究におけるAβの実験的な取扱いが困難なために、保存状態や実験条件・方法がわずかに異なることによる影響が大きく、Cu2+がAβの繊維形成を促進するという報告と、Aβの繊維形成を抑制するという報告が多数混在しており、Aβの凝集過程における金属イオンの具体的な役割については未だ理解されていない。本研究結果は、アミロイドペプチドが神経細胞細胞毒性を示すために一定の構造を取ることが必要であることを示すものであり、アルツハイマー病の発症原因の解明に資することが期待される。