2020 Fiscal Year Final Research Report
Structural organic chemistry in inhibitory mechanism of amyloid beta oligomerization
| Project/Area Number |
16H06194
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| Research Category |
Grant-in-Aid for Young Scientists (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Bioorganic chemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Keywords | 脳神経疾患 / アルツハイマー病 / 有機合成化学 / 漢方生薬 / オリゴマー / アミロイドβ / NMR / 質量分析 |
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| Outline of Final Research Achievements |
Aggregation of amyloid β42 (Aβ42) is one of the hallmarks of Alzheimer’s disease (AD). The mechanism of Aβ42 aggregation mainly consists of two phases, nucleation and elongation. Aβ42 oligomerization related to the elongation induces the neurotoxicity in AD pathogenesis. Herein we report that a preferable inhibition of toxic oligomer formation of Aβ42 by uncarinic acid C (UA-C), a triterpenoid from medicinal herbs, originates from a salt bridge of their carboxy groups with Aβ42-Lys16. We also proposed a method of classifying compounds into 9 groups based on their ability to modulate the nucleation and/or elongation phases. By screening natural product and shoyaku libraries or metabolomics, several compounds such as warfarin and quercetin 3-O-glucuronide that prevented Aβ42-induced neurotoxicity were identified. Moreover, we developed RNA aptamers with higher affinity toward Aβ42 oligomers, which strongly recognized brain oligomers.
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| Free Research Field |
生物有機化学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によって，生薬由来のウンカリン酸Cおよびワルファリン，RNAアプタマーがAβ42のオリゴマー化阻害能を示すことを初めて見いだした点において学術的意義があると考えている．また社会的意義としては，オリゴマー選択的な阻害物質の迅速スクリーニング法を提案し，既存薬であるワルファリンや身近な食品由来成分に治療薬としての可能性を見いだした点が挙げられる．今後，RNAアプタマーを用いた体外診断法に基づいた，オリゴマー化阻害剤による疾患予防が期待できる．これらの成果は，国際アルツハイマー病学会や日本食品科学工学会で招待講演などを行い，広く社会への還元を試みた．
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