| Project/Area Number |
16H05078
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
Oe Tomoyuki 東北大学, 薬学研究科, 教授 (10203712)
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| Co-Investigator(Kenkyū-buntansha) |
李 宣和 東北大学, 薬学研究科, 助教 (60519776)
佐藤 涼 東北大学, 薬学研究科, 助教 (20757166)
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| Research Collaborator |
SASAMOTO Kazuyuki
KATO Dai
YOKOYAMA Mizuki
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2017: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
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| Keywords | アミロイドβ / 化学修飾 / 質量分析 / 凝集 / プロテアーゼ抵抗性 |
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| Outline of Final Research Achievements |
Aggregation of Aβ40 was affected by chemical stresses: promoted by H2O2, but inhibited by MG, 4-hydroxy-2(E)-nonenal, 4-hydroxy-2(E)-nonenal, and methylglyoxal. Major modification sites were also identified as follows: Met32, N-term, His6,13,14, Arg5, Lys16, etc.
Non-aggregated Aβ40 was digested by neprilysin（NEP）or insulysin（IDE）for one day incubation. However, aggregated Aβ40 was not digested even by prolonged incubation (7 days). From the reaction mixture between non-aggregated Aβ40 and NEP/IDE, several long peptides (ca. 30) were identified. The major peptides (ca. 10 amino acids) were found to include the turn region (E22DVGS26), suggesting that NEP/IDE can recognize the secondary structure, not primary structure.
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| Academic Significance and Societal Importance of the Research Achievements |
アルツハイマー病は、アミロイドβ（Aβ）の構造変化・凝集に起因すると考えられ、現在まで種々の凝集トリガーが指摘されている。通常Aβは、インシュリン分解酵素IDE、脳内酵素NEPにより分解・除去される。一方、疫学調査で指摘されるアルツハイマー病の危険因子（糖尿病・老化）は、関連する糖化・酸化ストレスを通してAβを修飾する可能性がある。本研究では、Aβの糖化・酸化修飾に着目し、化学ストレス下での凝集変化と修飾体の構造、IDE・NEPの切断部位と凝集による抵抗性の獲得を明らかにした。本知見は、『アルツハイマー病』と『糖尿病』・『老化』との関連解明と治療ターゲット探索の一助となると考える。
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