Drug development for Alzheimer's disease targeting microglial dysfunction
Project/Area Number |
16K19776
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Psychiatric science
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Research Institution | Sapporo Medical University |
Principal Investigator |
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Project Period (FY) |
2016-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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Keywords | アルツハイマー 廟 / 認知症 / ミクログリア / アルツハイマー 病 / アミロイドβ / SOCS3 / 炎症 / アルツハイマー病 / 脳神経疾患 / 痴呆 |
Outline of Final Research Achievements |
We study the molecular mechanism of Alzheimer’s disease (AD), and are trying to develop novel therapy for AD. Accumulation of activated microglia in and around senile plaques has been demonstrated in autopsied brains from AD patients, and considered to modulate amyloid β clearances and inflammation. Our research suggested that microglial activation changes with progression of AD expressing several makers molecule. Activated microglia in the advanced stage of AD model showed higher expression levels of CD14. On the other hands, anti-inflammatory factor, SOCS3, is also up regulated in microglia in advanced AD model. We demonstrated therapeutic effects of mesenchymal stromal cells (MSCs) using AD model mice. We showed that MSC treatment enhanced amyloid beta clearance by microglia.
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Academic Significance and Societal Importance of the Research Achievements |
今回我々は,ミクログリアによる炎症の抑制ならびにAβの取り込み機構としてSOCS3やTLR4/CD14複合体の役割を解明した.これらの機構を解明することはミクログリアを標的とした新規治療薬を開発する上で重要な知見である.加えて,MSC移植治療が実際にCD14の発現を誘導し,ミクログリアによるAβクリアランスを促進することを示した.MSC移植治療はすでにGVHDや脊髄損傷の治療で臨床応用が始まっており,今回の知見はADに対する臨床応用を検討する上で重要な基礎データとなる.
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Report
(5 results)
Research Products
(9 results)
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[Journal Article] CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia Through A Clathrin-Mediated Pathway.2019
Author(s)
Fujikura M, Iwahara N, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Manabe T, Matsushita T, Suzuki S, Shimohama S.
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Journal Title
J Alzheimers Dis.
Volume: 68
Issue: 1
Pages: 323-337
DOI
Related Report
Peer Reviewed
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[Journal Article] Evaluation of Mitochondrial Oxidative Stress in the Brain of a Transgenic Mouse Model of Alzheimer's Disease by in vitro Electron Paramagnetic Resonance Spectroscopy.2019
Author(s)
Manabe T, Matsumura A, Yokokawa K, Saito T, Fujikura M, Iwahara N, Matsushita T, Suzuki S, Hisahara S, Kawamata J, Suzuki H, Emoto MC, Fujii HG, Shimohama S.
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Journal Title
Journal of Alzheimer's disease
Volume: 67
Issue: 3
Pages: 1079-1087
DOI
Related Report
Peer Reviewed
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[Journal Article] Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice.2017
Author(s)
Iwahara N, Hisahara S, Kawamata J, Matsumura A, Yokokawa K, Saito T, Fujikura M, Manabe T, Suzuki H, Matsushita T, Suzuki S, Shimohama S.
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Journal Title
J Alzheimers Dis.
Volume: 55
Pages: 1235-1247
Related Report
Peer Reviewed / Acknowledgement Compliant
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