Prevention of progressive dementia by drug-repositioning of rifampicin
| Project/Area Number |
19K07847
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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 51030:Pathophysiologic neuroscience-related
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| Research Institution | Osaka City University |
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Principal Investigator |
Umeda Tomohiro 大阪市立大学, 大学院医学研究科, 特任講師 (70549790)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 神経変性疾患 / 認知症 / タウ / 予防薬・治療薬 / リファンピシン / 神経病理伝播 / rifampicin / tau oligomers / propagation / progression / tauopathy / 認知症進行の抑制 / ドラッグリポジショニング / Rifampicin / トランスレーショナルリサーチ / アルツハイマー病 |
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| Outline of Research at the Start |
アルツハイマー病の2つの原因分子アミロイドβとtauを同時に抑制可能な既存医薬品rifampicinが、疾患の進行を抑制できる可能性について検証する。アルツハイマー病では、脳に蓄積したアミロイドβの影響で生じる毒性tauが、神経変性を引き起こすと同時に、隣接する細胞間を伝播して脳内で変性領域を拡大することが知られている。このメカニズムに基づき、アミロイドβとtauの毒性体を同時に抑制できるrifampicinが、①細胞内での毒性tauの形成、②分泌後の毒性tau、③毒性tauの細胞内取り込み、をそれぞれ低下させることを培養細胞系で確認し、tau伝播モデルマウスでその伝播抑制効果を検証する。
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| Outline of Final Research Achievements |
Tau propagation is a mechanism underlying the intracerebral spreading of tau pathology in Alzheimer’s disease (AD). Recent studies suggest that tau oligomers participate in this process. We have showed that intranasal rifampicin (RFPi.n.) inhibits tau oligomer accumulation in mice. In this study, we examined the effects of RFPi.n. on tau propagation in a new mouse model. A tau oligomer-rich frc. prepared from the brain of an AD patient was injected into a unilateral hippocampus of Tau264 mice that express both 3R- and 4R-WT human tau. RFPi.n. was started 1 week after the injection and performed 3 times a week for 24 weeks. Cognitive function and tau pathology were assessed by the Morris water maze test and IHC. RFPi.n. inhibited the spreading of tau oligomers and neurofibrillary tangle formation. Synapse and neuronal loss were also prevented, and cognitive function remained normal. The results suggest that RFPi.n. could be a promising remedy that halts the progression of tauopathy.
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| Academic Significance and Societal Importance of the Research Achievements |
経鼻rifampicinはtau病理伝播を抑制することで、脳内変性領域の拡大と記憶障害を阻止した。経鼻rifampicinが、病理形成前での予防的効果だけでなく、疾患発症後の進行をも抑止できる可能性が示された。Drug repositioningによる効果的かつready-to-useな認知症予防薬・治療薬となりえる。
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Report
(4 results)
Research Products
(5 results)
