Development of novel amyloid-beta aggregation inhibitors based on the constituents of Perilla frutescens var. crispa, and their mechanism of action

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K01909
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biomolecular chemistry
• Research Institution: Muroran Institute of Technology
• Principal Investigator: UWAI KOJI 室蘭工業大学, 大学院工学研究科, 准教授 (80347905)
• Research Collaborator: TOKURAKU Kiyotaka ; HAYASHI Takafumi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: アルツハイマー病 / アミロイドβ / ロスマリン酸 / 凝集阻害 / シソ / 構造活性相関

Outline of Final Research Achievements

In this study, amyloid-beta aggregation inhibitory activities of stnthesized rosmarinic acid derivatives were evaluated by miclo-litter high-through put screening system (MSHTS) and ThT method, and docking simulation between Abeta and the derivatives were also studied. Results suggested that the compounds showed higer activity owned both lipophilic moiety and phenolic hydroxyls and their CLogP values were nearly equal to values of general drugs acted to central nervous system. Considering the difference of the activities obtained by two different methods (MSHTS and ThT), the derivatives showed the activity by two defferent mechanisms based on their chemical structure. The additional detailed biochemical and spectroscopic studies, the derivatives were devided to two groups: one was the compounds that inhibited the initial stage of the aggregation and another was the compounds that inhibited the aggregation between middle size aggregates.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病 (AD) の原因の一つである患者の脳内でのアミロイドβ（Aβ）タンパクの凝集・蓄積を強く阻害するアオジソの，主要な活性成分の一つであるロスマリン酸をもとにした様々な誘導体を合成し，その凝集阻害機構を検討した．その結果，ロスマリン酸誘導体の構造の違いにより，凝集体の中でも脳の神経細胞に対して強い毒性を示す可溶性オリゴマーの形成に影響することが明らかになった．ADの患者数は世界的に増加し続け，その克服が喫緊の課題となっているが，現状では対症療法しかなく，根本的な治療法が求められている．本研究で得られた新しい物質はADの予防や治療，またAD発症の原因研究に有用であると考えられる．