Drug repositioning approaches for the development of new treatments for Alzheimer's disease
| Project/Area Number |
16K08254
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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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| Research Field |
Biological pharmacy
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| Research Institution | Doshisha University |
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Principal Investigator |
Urano Yasuomi 同志社大学, 生命医科学部, 准教授 (00546674)
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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 |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | アルツハイマー病 / 脂質代謝 / 細胞死 / ACAT (SOAT) / ドラッグリポジショニング / 24S-hydroxycholesterol / オキシステロール / ACAT / 脂質 / 神経科学 |
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| Outline of Final Research Achievements |
We have previously demonstrated that acyl-coA:cholesterol acyltransferase 1 (ACAT1) specific inhibitor K-604 reduced Amyloid β (Aβ) production and also suppressed the brain-specific oxysterol, 24S-hydroxycholesterol (24S-OHC)-induced neuronal cell death. In this study, we found that K-604 treatment inhibited Aβ production in a secretase substrate-specific manner. We also established the successful efficient delivery of a single dose of K-604 to the brain via the intranasal route. We further identified four long-chain unsaturated fatty acids with which 24S-OHC is esterified by ACAT. Accumulation of 24S-OHC esters affected the structure and function of endoplasmic reticulum, resulting in induction of neuronal cell death.
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| Academic Significance and Societal Importance of the Research Achievements |
現行のAD治療薬は記憶力の低下を遅らせる対症療法薬しか存在せず、根本治療薬の開発には成功していない。K-604によるACAT1の選択的阻害は、これまでのアプローチと全く異なる新たな視点から、AD病態に関与するAβ産生の抑制、さらに脂質誘導性細胞死の抑制という相乗的な効果をもつことが確認され、発症を予防且つ改善する治療薬の開発を目指す点において根本的な治療薬となる可能性をもつことが考えられた。またK-604は臨床試験まで進んだ実績から、安全性評価は高度に保証されており、本研究で開発した経鼻投与法を応用したドラッグリポジショニングとしての観点に立てば、より実用化の可能性が優位と位置づけられる。
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Report
(4 results)
Research Products
(18 results)
