Examining the risk of developing Alzheimer's disease induced by decreased expression of ILEI
| Project/Area Number |
20K16491
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
WATANABE Naoki 滋賀医科大学, 神経難病研究センター, 助教 (60769339)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | アルツハイマー病 / Amyloid-β / ILEI / 遺伝子発現制御 / 老年期認知症 |
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| Outline of Research at the Start |
Alzheimer病(AD)の基本病態はamyloid-β (Aβ)ペプチドの脳内蓄積であるが、この要因は未だ解明されておらず、発症前に開始すべき根本的治療の開発には至っていない。代表者らは、Aβ産生抑制タンパク質ILEIを見出し、ILEIの加齢等に伴う発現低下がAβ蓄積を誘発することが示唆された。本研究課題では、孤発性ADのリスク要因としてのILEI発現低下に焦点を当て、老化やADに伴う脳ILEI発現低下機構の解明と、誘導性コンディショナルノックアウトマウスを用いた検証により、Aβ蓄積の一次的要因の一端を解明し、Aβ蓄積に対するILEIを標的とした先制医療の実現に資する知見を得る。
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| Outline of Final Research Achievements |
Reporter assay revealed two transcriptionally active regions of ILEI gene near the transcription start site, and transcription factors SP1 and EBF1 were found by database search, knockdown, and forced expression. RNA-seq revealed decreased ILEI in AD brain and decreased binding of SP1 and EBF1 to this region in AD brain.
App(NL-F);ILEI-cKO mice, which can be induced with a neural-specific defect, were generated and crossed with the App(NL-F) strain, and after defect induction at 3 and 6 months of age, increased Aβ deposition was observed in the brains of App(NL-F);ILEI-cKO mice compared to the control mice at 14 months of age by immunohistochemical staining and ELISA. Y-maze test showed that the working memory of App(NL-F);ILEI-cKO mice was impaired compared to the control mice after 10 months of age.
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| Academic Significance and Societal Importance of the Research Achievements |
ILEIはγセクレターゼ活性を阻害せず、Aβの基質APP-C99の不安定化によりAβ産生を減少させる。このためγセクレターゼによる治療法開発で従来問題になったNotch阻害による副作用を回避した治療標的として有望であり、脳内Aβ蓄積のリスク評価を標的としたバイオマーカーとしても期待できる。ILEIの特異な活性や脳内発現について申請者らが初めて見出したもので、本研究は独自性が高く、今後さらに新たな研究領域を生む創造性も期待できる。将来、高齢者スクリーニングとしてILEIを含めたバイオマーカーを評価し、リスクを推定した上で、予防的治療を加えるという認知症の先制医療の実現を目指し、研究を進めている。
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Report
(4 results)
Research Products
(14 results)
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[Journal Article] Extracellular release of ILEI/FAM3C and amyloid-β is associated with the activation of distinct synapse subpopulations.2021
Author(s)
Nakano M, Mitsuishi Y, Liu L, Watanabe N, Hibino E, Hata S, Saito T, Saido C T, Murayama S, Kasuga K, Ikeuchi K, Suzuki T, Nishimura M
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Journal Title
Journal of Alzheimer’s disease
Volume: 80
Issue: 1
Pages: 159-174
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Generation of transgenic cynomolgus monkeys overexpressing the gene for amyloid-β precursor protein2020
Author(s)
Seita Y, Morimura T, Watanabe N, Iwatani C, Tsuchiya H, Nakamura S, Suzuki T, Yanagisawa D, Tsukiyama T, Nakaya M, Okamura E, Muto M, Ema M, Nishimura M, Tooyama I.
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Journal Title
Journal of Alzheimer's Disease
Volume: -
Issue: 1
Pages: 45-60
DOI
NAID
Related Report
Peer Reviewed / Open Access
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