2022 Fiscal Year Final Research Report
Establishing quantitative and comprehensive methods for analyzing vesicular traffic impairment to identify the drug candidates for Alzheimer's disease
| Project/Area Number |
20K07014
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Okayama University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
橋本 唯史 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第四部, 部長 (30334337)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | アルツハイマー病 / 小胞輸送障害 / 神経変性疾患 / βCTF / Aβ / 脂質輸送酵素 / リピッドフリッパーゼ |
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| Outline of Final Research Achievements |
Recently, it has been shown that vesicular trafficking impairments occur as early Alzheimer's disease (AD) pathology and to trigger other AD pathologies. Vesicular trafficking impairments are triggered by endosomal accumulation of β-secretase cleaved carboxyl terminal fragment (βCTF), a metabolite formed when APP is cleaved by AD associated enzyme, β-secretase.
In this study, we elucidated the mechanism by which βCTF binds to TMEM30A, a lipid flippase (LF) component that regulates vesicular transport, and impairs vesicular transport, established an efficient measurement system for LF activity and a method to analyze vesicular transport impairment, and identified T-RAP, a small peptide derived from the TMEM30A structure, as a therapeutic candidate. Because T-RAP targets AD pathology-specific disorders, it is expected to reduce side effects and may be a new category of drug with multifunctional properties.
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| Free Research Field |
薬理学
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| Academic Significance and Societal Importance of the Research Achievements |
AD発症の最有力な仮説であるアミロイド仮説においても、Aβ産生・凝集・毒性発揮などの多くの病態が含まれるが，現状多くの治療薬候補は単一標的であり、その治療効果も限定的である．
本研究は，アミロイド仮説を補完できる交通渋滞仮説の分子機構解明に迫っており，さらにAD病態に対し特異性・多機能的治療効果を持ち，複雑なAD病態に対応でき、副作用の少ない薬物創出の可能性を提示している．神経細胞はその長い構造上，輸送にコストがかかり，小胞輸送障害は筋萎縮性側索硬化症（ALS）やパーキンソン病発症においても発症リスクに寄与しており，本技術の開発によりこれらの神経変性疾患にも応用できる技術の開発が期待できる．
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