Establishment of the system eliminating amyloid-beta across the blood-brain barrier

• Project/Area Number: 26461271
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Yamaguchi University
• Principal Investigator: SANO Yasuteru 山口大学, 医学(系)研究科(研究院), 助教 (20379978)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 血液脳関門 / アルツハイマー病

Outline of Final Research Achievements

The clearance of amyloid β from the brain could be a novel therapeutic target for Alzheimer’s disease (AD). Although LRP1 and ABC transporters were the Aβ transporters at the blood-brain barrier (BBB), conflicting data exist regarding the contribution of these proteins to the clearance of Aß through the BBB. In this study, we examined the expression of LRP1, p-glycoprotein, ABCG2 in the human brain pericytes (HBPCT) and human brain microvascular endothelial cells (HBMECs) using real time PCR, western blot, and immunostaining analyses. LRP1 were mainly expressed in HBPCT, not HBMECs. On the other hand, P-glycoprotein and ABCG2 were predominantly expressed in HBMECs. In addition, we disclosed that RAP, an inhibitor of LRP1, deceased the uptake of FAM-Aβ40 into HBPCT cells. These results indicated that Aβ could be transported across not only HBMEC but also HBPCTs via these receptor and transporter.

Research Products

• [Journal Article] Establishment of a New Conditionally Immortalized Human Skeletal Muscle Microvascular Endothelial Cell Line (2017)
  • Author(s): Sano, H. Sano, Y. Ishiguchi, E. Shimizu, F. Omoto, M. Maeda, T. Nishihara, H. Takeshita, Y. Takahashi, S. Oishi, M. Kanda, T.
  • Journal Title: Journal of Cellular Physiology Volume: 印刷中 Issue: 12 Pages: 3286-3295
  • DOI: 10.1002/jcp.25772
  • Peer Reviewed
• [Journal Article] Astrocytes contribute to Aβ-induced blood brain barrier damage through activation of endothelial MMP9. (2017)
  • Author(s): Spampinato SF, Merlo S, Sano Y, Kanda T, Sortino MA.
  • Journal Title: J Neurochem. Volume: 印刷中 Issue: 3 Pages: 464-477
  • DOI: 10.1111/jnc.14068
  • Peer Reviewed
• [Journal Article] Effects of neuromyelitis optica-IgG at the blood-brain barrier in vitro. (2016)
  • Author(s): Takeshita Y, Obermeier B, Cotleur AC, Spampinato SF, Shimizu F, Yamamoto E, Sano Y, Kryzer TJ, Lennon VA, Kanda T, Ransohoff RM.
  • Journal Title: Neurol Neuroimmunol Neuroinflamm. Volume: 4 Issue: 1
  • DOI: 10.1212/nxi.0000000000000311
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rituximab-associated Progressive Multifocal Leukoencephalopathy Derived from Non-Hodgkin Lymphoma: Neuropathological Findings and Results of Mefloquine Treatment (2015)
  • Author(s): Sano Y, Nakano Y, Omoto M, Takao M, Ikeda E, Oga A, Nakamichi K, Saijo M, Maoka T, Sano H, Kawai M, Kanda T.
  • Journal Title: Internal Medicine Volume: 54 Issue: 8 Pages: 965-970
  • DOI: 10.2169/internalmedicine.54.2308
  • NAID: 130005065265
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli? (2015)
  • Author(s): Spampinato SF, Obermeier B, Cotleur A, Love A, Takeshita Y, Sano Y, Kanda T, Ransohoff RM.
  • Journal Title: PLoS One. Volume: 10 Issue: 7 Pages: e0133392-e0133392
  • DOI: 10.1371/journal.pone.0133392
  • Peer Reviewed
• [Journal Article] Pertussis Toxin Exploits Specific Host Cell Signaling Pathways for Promoting Invasion and Translocation of Escherichia coli K1 RS218 in Human Brain-derived Microvascular Endothelial Cells. (2015)
  • Author(s): Karassek S, Starost L, Solbach J, Greune L, Sano Y, Kanda T, Kim K, Schmidt MA.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 41 Pages: 24835-24843
  • DOI: 10.1074/jbc.m115.650101
  • Peer Reviewed
• [Journal Article] Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis. (2015)
  • Author(s): Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0121488-e0121488
  • DOI: 10.1371/journal.pone.0121488
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Markedly Increased IP-10 Production by Blood-Brain Barrier in Neuromyelitis Optica. (2015)
  • Author(s): Shimizu F, Nishihara H, Sano Y, Takeshita Y, Takahashi S, Maeda T, Takahashi T, Abe M, Koga M, Kanda T.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0122000-e0122000
  • DOI: 10.1371/journal.pone.0122000
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An in vitro blood-brain barrier model combining shear stress and endothelial cell/astrocyte co-culture (2014)
  • Author(s): Takeshita Y, Obermeier B, Cotleur A, Sano Y, Kanda T, Ransohoff RM
  • Journal Title: J Neurosci Methods Volume: ２３２ Pages: 165-72
  • DOI: 10.1016/j.jneumeth.2014.05.013
  • Peer Reviewed / Open Access
• [Presentation] 皮膚筋炎の治療における副腎皮質ステロイドの筋微小血管内皮細胞への影響 (2016)
  • Author(s): 佐野泰照，尾本雅俊，石口絵梨，西原秀昭，竹下幸男，前田敏彦，古賀道明，神田隆
  • Organizer: 第28回日本神経免疫学会学術集会
  • Place of Presentation: 長崎県，長崎市（長崎ブリックホール）
  • Year and Date: 2016-09-29
• [Presentation] The effects of glucocorticoid to endomysial microvessels in the treatment for dermatomyositis. (2016)
  • Author(s): Sano Y, Omoto M, Maeda T, Nishihara H, Takeshita Y, Kanda T
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 兵庫県，神戸市（神戸国際会議場）
  • Year and Date: 2016-05-18
• [Presentation] Establishment of a new human muscle microvascular endothelial cell line. (2016)
  • Author(s): Sano Y, Omoto M, Kanda T
  • Organizer: American Academy of Neurology (AAN) 68th Annual Meeting.
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-04-15
  • Int'l Joint Research
• [Presentation] ヒト血液脳関門を介したアミロイドβ蛋白排出におけるABC輸送体の役割 (2015)
  • Author(s): 佐野 泰照, 前田 敏彦, 安部 真彰, 川井 元晴, 神田 隆
  • Organizer: 第34回日本認知症学会学術集会
  • Place of Presentation: 青森市（リンクステーションホテル青森）
  • Year and Date: 2015-10-02
• [Presentation] ヒト筋微小血管内皮細胞の細胞生物学的特徴 (2015)
  • Author(s): 佐野 泰照, 尾本 雅俊, 佐野 宏徳, 前田 敏彦, 安部 真彰, 西原 秀昭, 神田 隆
  • Organizer: 第27回日本神経免疫学会学術集会
  • Place of Presentation: 岐阜市（長良川国際会議場）
  • Year and Date: 2015-09-15
• [Presentation] Establishment of a new human muscle microvascular endothelial cell line (2015)
  • Author(s): Yasuteru Sano, Hironori Sano, Toshihiko Maeda, Masaaki Abe, Masatoshi Omoto, and Takashi Kanda
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟市（ホテル日航新潟）
  • Year and Date: 2015-05-20
• [Presentation] Analysis of factors regulating the expression of AQP4 in human astrocyte (2014)
  • Author(s): Yasuteru Sano, Mariko Oishi, Hiroyo Haruki, Fumitaka Shimizu, Masaaki Abe, and Takashi Kanda
  • Organizer: 12th International Congress of NeuroImmunology
  • Place of Presentation: Ｍａｉｎｚ， Ｇｅｒｍａｎｙ
  • Year and Date: 2014-11-09 – 2014-11-13
• [Presentation] Role ATP-binding cassette transporters in efflux of amyloid-β at the human blood-brain barrier (2014)
  • Author(s): Yasuteru Sano, Kazuyuki Saito, Masaaki Abe, Hideaki Nishihara, and Takashi Kanda
  • Organizer: Neuroscience 2014
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 血液脳関門のAβ蛋白輸送担体を制御する因子の検索 (2014)
  • Author(s): 佐野泰照，清水文崇，前田敏彦，安部真彰，大石真莉子，佐野宏徳，西原秀昭，神田 隆
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場（福岡市）
  • Year and Date: 2014-05-21 – 2014-05-24