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Development of anti-glycosylation agents for Alzheimer disease

Research Project

Project/Area Number 15H04271
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Nerve anatomy/Neuropathology
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

IHARA MASAFUMI  国立研究開発法人国立循環器病研究センター, 病院, 部長 (00372590)

Co-Investigator(Kenkyū-buntansha) 周 びん  公益財団法人先端医療振興財団, その他部局等, その他 (00598774)
飯田 秀博  国立研究開発法人国立循環器病研究センター, 病院, 非常勤研究員 (30322720)
植田 初江  国立研究開発法人国立循環器病研究センター, 病院, 部長 (40522983)
Co-Investigator(Renkei-kenkyūsha) TOMIMOTO Hidekazu  三重大学, 医学研究科, 教授 (80324648)
ONO Masahiro  京都大学, 薬学研究科, 教授 (80336180)
Research Collaborator SAITO Satoshi  
YAMAMOTO Yumi  
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Keywordsタキシフォリン / 抗糖化作用 / アルツハイマー病 / タウ / 脳アミロイド血管症 / 脳神経疾患 / 神経科学 / 脳・神経 / 痴呆 / 病理学 / 認知症 / オリゴマー / 抗糖化薬 / アミロイド / 脳循環障害 / 抗糖化 / シロスタゾール / アミロイドβ
Outline of Final Research Achievements

Taxifolin, a biologically active polyphenol with antiglcation activity, was found to suppress amyloid beta-induced neurodegeneration and restored congnitive impairment in an animal model of Alzheimer's disease. In addition, crossbleeding of amyloid beta-overexpressing mice with tau-overexpressing mice showed that vascular amyloid beta accelerated tau accumulation, suggesting that taxifolin can suppress tau accumulation in the brain. The researchers are conducting a clinical trial using cilostazol for patients with mild cognitive impairment. Based on the findings shown above, we are planning to start a clinical trial of taxifolin for patients with cognitive impairment.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (32 results)

All 2018 2017 2016 2015 Other

All Int'l Joint Research (3 results) Journal Article (17 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 17 results,  Open Access: 6 results,  Acknowledgement Compliant: 4 results) Presentation (7 results) (of which Int'l Joint Research: 2 results,  Invited: 4 results) Remarks (3 results) Patent(Industrial Property Rights) (2 results)

  • [Int'l Joint Research] Newcastle University/Edinburgh University/Southampton University(United Kingdom)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Institute of Primate Research(Kenya)

    • Related Report
      2015 Annual Research Report
  • [Int'l Joint Research] Louisville University(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Dysregulation of RNF213 promotes cerebral hypoperfusion2018

    • Author(s)
      Morimoto T, Enmi J, Hattori Y, Iguchi S, Saito S, Harada K, Okuda H, Mineharu Y, Takagi Y, Youssefian S, Iida H, Miyamoto S, Ihara M, Kobayashi H, Koizumi A.
    • Journal Title

      Sci Rep

      Volume: 8 Issue: 1 Pages: 3607-3607

    • DOI

      10.1038/s41598-018-22064-8

    • NAID

      120006510289

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Swallowing-induced displacement of the carotid artery as a risk of stroke: Flip-flop phenomenon2017

    • Author(s)
      Kinoshita Naoto、Saito Kozue、Tanaka Tomotaka、Kajimoto Katsufumi、Yamagami Hiroshi、Morita Yoshiaki、Ihara Masafumi、Nagatsuka Kazuyuki
    • Journal Title

      Neurology

      Volume: 89 Issue: 15 Pages: 1643-1644

    • DOI

      10.1212/wnl.0000000000004492

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Long-term cilostazol treatment reduces gliovascular damage and memory impairment in a mouse model of chronic cerebral hypoperfusion2017

    • Author(s)
      Kitamura Akihiro、Manso Yasmina、Duncombe Jessica、Searcy James、Koudelka Juraj、Binnie Margaret、Webster Scott、Lennen Ross、Jansen Maurits、Marshall Ian、Ihara Masafumi、Kalaria Raj N.、Horsburgh Karen
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 4299-4299

    • DOI

      10.1038/s41598-017-04082-0

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy2017

    • Author(s)
      Satoshi Saito, Yumi Yamamoto, Takakuni Maki, Yorito Hattori, Hideki Ito, Katsuhiko Mizuno, Mariko Harada-Shiba, Raj N. Kalaria, Masanori Fukushima, Ryosuke Takahashi, Masafumi Ihara
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 5 Issue: 1 Pages: 26-26

    • DOI

      10.1186/s40478-017-0429-5

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Frontal White Matter Hyperintensities, Clasmatodendrosis and Gliovascular Abnormalities in Ageing and Post-stroke Dementia2016

    • Author(s)
      13.Chen A, Akinyemi RO, Hase Y, Firbank MJ, Ndung’u MN, Foster V, Craggs LJL, Washida K, Okamoto Y, Thomas AJ, Polvikosk TM, Allan JM, Oakley AE, O’Brien JT, Horsburgh K, Ihara M, Kalaria RN
    • Journal Title

      Brain

      Volume: 139 Issue: 1 Pages: 242-258

    • DOI

      10.1093/brain/awv328

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory2016

    • Author(s)
      Kitamura A, Saito S, Maki A, Ayaki T, Oishi N, Kalaria RN, Hattori Y, Yamamoto Y, Urushitani M, Horsburgh K, Fukuyama H, Takahashi R, Ihara M
    • Journal Title

      J Cereb Blood Flow Metab

      Volume: - Issue: 9 Pages: 1592-1602

    • DOI

      10.1177/0271678x15606717

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hemisphere asymmetry of response to treatment in an Alzheimer’s disease mouse model2016

    • Author(s)
      Manousopoulou A, Saito S, Yamamoto Y, Al-Daghri NM, Ihara M, Carare RO, Garbis SD
    • Journal Title

      J Alzheimers Dis

      Volume: 21 Issue: 2 Pages: 333-338

    • DOI

      10.3233/jad-151078

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Interaction between cerebrovascular disease and Alzheimer pathology2016

    • Author(s)
      Saito S, Ihara M
    • Journal Title

      Curr Opin Psychiatry

      Volume: 29 Issue: 2 Pages: 168-173

    • DOI

      10.1097/yco.0000000000000239

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stroke Injury, cognitive Impairment and vascular dementia2016

    • Author(s)
      Kalaria RN, Akinyemi R, Ihara M
    • Journal Title

      Biochim Biophys Acta

      Volume: - Issue: 5 Pages: 915-925

    • DOI

      10.1016/j.bbadis.2016.01.015

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans.2016

    • Author(s)
      Hattori Y, Enmi J, Iguchi S, Saito S, Yamamoto Y, Tsuji M, Nagatsuka K, Kalaria RN, Iida H, Ihara M
    • Journal Title

      Journal of the American Heart Association

      Volume: 5 Issue: 2

    • DOI

      10.1161/jaha.115.002757

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Emerging evidence for pathogenesis of sporadic cerebral small vessel disease2016

    • Author(s)
      Ihara M, Yamamoto Y
    • Journal Title

      Stroke

      Volume: 47 Issue: 2 Pages: 554-560

    • DOI

      10.1161/strokeaha.115.009627

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Influence of low-dose aspirin on cerebral amyloid angiopathy in mice2016

    • Author(s)
      Hattori Y, Maki T, Saito S, Yamamoto Y, Nagatsuka K, Ihara M
    • Journal Title

      J Alzheimers Dis

      Volume: - Issue: 3 Pages: 1037-1045

    • DOI

      10.3233/jad-160013

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Immunolocalisation of PDGFRβ and pericytes in CADASIL2015

    • Author(s)
      Craggs LJL, Fenwick R, Oakley AE, Ihara M, Kalaria RN
    • Journal Title

      Neuropath Appl Neurobiol

      Volume: 41 Issue: 4 Pages: 557-570

    • DOI

      10.1111/nan.12188

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Mild cognitive impairment: at the crossroad of neurodegeneration and vascular dysfunction2015

    • Author(s)
      Saito S, Yamamoto Y, Ihara M
    • Journal Title

      Curr Alzheimer Res

      Volume: 12 Issue: 6 Pages: 507-512

    • DOI

      10.2174/1567205012666150530202508

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: what are the roadblocks and how can they be overcome?2015

    • Author(s)
      Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, Chen W, Ding Y, Mudher A, Padjen AL, Mukaetova-Ladinska E, Ihara M, Srivastava E, Srivastava MVP, Masters CL, Kalaria RN, Anand A
    • Journal Title

      J Alzheimer Dis

      Volume: 47 Issue: 4 Pages: 815-843

    • DOI

      10.3233/jad-150136

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Structure-Activity Relationship Study of Heterocyclic Phenylethenyl and Pyridinylethenyl Derivatives as Tau-Imaging Agents that Selectively Detect Neurofibrillary Tangles in Alzheimer’s Disease Brains2015

    • Author(s)
      Matsumura K, Ono M, Kitada A, Watanabe H, Yoshimura M, Iikuni S, Kimura H, Okamoto Y, Ihara M, Saji H.
    • Journal Title

      J Med Chem

      Volume: 58 Issue: 18 Pages: 7241-7257

    • DOI

      10.1021/acs.jmedchem.5b00440

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain.2015

    • Author(s)
      Kim J, Yoon H, Horie T, Burchett JM, Restivo JL, Rotllan N, Ramírez CM, Verghese PB, Ihara M, Hoe HS, Esau C, Fernández-Hernando C, Holtzman DM, Cirrito JR, Ono K, Kim J.
    • Journal Title

      J Neurosci.

      Volume: 35(44) Issue: 44 Pages: 14717-26

    • DOI

      10.1523/jneurosci.2053-15.2015

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 慢性脳低灌流はタウ病理を加速させる: 脳血管アミロイド血管症とタウとの関連2017

    • Author(s)
      齊藤聡、 山本由美、 高橋良輔、 猪原匡史
    • Organizer
      脳循環代謝学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ドラッグ・リポジショニングの手法を用いた軽度認知障害に対する創薬戦略2015

    • Author(s)
      猪原匡史
    • Organizer
      第38回分子生物学会年会・第88回生化学会大会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 血管病を標的とした認知症治療2015

    • Author(s)
      猪原匡史
    • Organizer
      第5回認知症予防学会
    • Place of Presentation
      神戸
    • Year and Date
      2015-09-27
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Animal Model of VCI2015

    • Author(s)
      Masafumi Ihara
    • Organizer
      Vas-Cog International
    • Place of Presentation
      Tokyo
    • Year and Date
      2015-09-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Vascular Cognitive Impairment2015

    • Author(s)
      猪原匡史
    • Organizer
      第20回認知神経科学会
    • Place of Presentation
      東京
    • Year and Date
      2015-08-09
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Bone morphogenetic protein‐4 expression by pericytes correlates with white matter damage in dementing disorders2015

    • Author(s)
      Masafumi Ihara
    • Organizer
      Annual Meeting of the Japan Neuroscience Society
    • Place of Presentation
      Kobe
    • Year and Date
      2015-07-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] Experimental evidence linking vascular factors to Alzheimer's disease2015

    • Author(s)
      Masafumi Ihara
    • Organizer
      Alzheimer's Association International Conference (AAIC)
    • Place of Presentation
      Washington DC, USA
    • Year and Date
      2015-07-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 国立循環器病研究センター病院・脳神経内科

    • URL

      http://www.ncvc.go.jp/hospital/section/scd/cerebrovascular/b-group.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 国立循環器病研究センター脳神経内科

    • URL

      http://www.ncvc.go.jp/hospital/section/scd/cerebrovascular/b-group.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] 脳血管研究グループについて

    • URL

      http://www.ncvc.go.jp/hospital/pro/info/neurovascular/

    • Related Report
      2015 Annual Research Report
  • [Patent(Industrial Property Rights)] 認知症の予防及び/又は治療のための薬剤2016

    • Inventor(s)
      猪原匡史,齊藤聡,松本忠冒, 福島雅典
    • Industrial Property Rights Holder
      猪原匡史,齊藤聡,松本忠冒, 福島雅典
    • Industrial Property Rights Type
      特許
    • Filing Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 放射性ハロゲン標識ピリド[1,2-a]ベンゾイミダゾール誘導体化合物2015

    • Inventor(s)
      小野 正博、佐治 英郎、猪原匡史、松本博樹、関育也
    • Industrial Property Rights Holder
      小野 正博、佐治 英郎、猪原匡史、松本博樹、関育也
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2015-161472
    • Filing Date
      2015-08-19
    • Related Report
      2015 Annual Research Report

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Published: 2015-04-16   Modified: 2022-09-26  

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