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A study to elucidate the mechanism by which the longevity gene product SIRT1 confers neuroprotection

Research Project

Project/Area Number 25640031
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Nerve anatomy/Neuropathology
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

IHARA Masafumi  独立行政法人国立循環器病研究センター, 病院, 医長 (00372590)

Project Period (FY) 2013-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords長寿遺伝子 / サーチュイン / SIRT1 / 血管性認知症 / 脳梗塞 / 脳卒中 / 内皮型一酸化窒素合成酵素 / 血液脳関門 / Sirt1 / 両側総頸動脈狭窄術 / 一酸化窒素 / 脳循環予備能 / レスベラトロール
Outline of Final Research Achievements

SIRT1 belongs to the sirtuin family of protein deacetylases which mediate extensions of lifespan and suppress cerebrovascular diseases in model organisms. We hypothesized that neurovascular protection incorporates the broad-range effects of SIRT1. To test this, we generated Sirt1-overexpressing (Sirt1-Tg) mice driven by a prion promoter to determine whether Sirt1-Tg mice protect consequences of cerebral hypoperfusion in vivo. Cerebral hypoperfusion induced by bilateral common carotid artery stenosis caused memory impairment and histological changes in wild-type mice. However, these phenotypes were rescued in Sirt1-Tg mice, where cerebral blood flow was maintained even poststenosis. Brain endothelial nitric oxide synthase was acetylated after cerebral hypoperfusion in wild-type littermates but remained unacetylated in Sirt1-Tg mice. Our results indicate that neurovascular endothelial SIRT1 potentiation upregulates the nitric oxide system and counters cerebral hypoperfusion injury.

Report

(3 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • Research Products

    (35 results)

All 2015 2014 2013 Other

All Journal Article (24 results) (of which Peer Reviewed: 24 results,  Acknowledgement Compliant: 2 results,  Open Access: 2 results) Presentation (10 results) (of which Invited: 6 results) Remarks (1 results)

  • [Journal Article] A novel mouse model of subcortical infarcts with dementia.2015

    • Author(s)
      Hattori Y, Enmi J, Kitamura A, Yamamoto Y, Saito S, Takahashi Y, Iguchi S, Tsuji M, Yamahara K, Nagatsuka K, Iida H, Ihara M
    • Journal Title

      The Journal of Neuroscience

      Volume: 35 Issue: 9 Pages: 3915-3928

    • DOI

      10.1523/jneurosci.3970-14.2015

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] SIRT1 attenuates severe ischemic damage by preserving cerebral blood flow.2015

    • Author(s)
      Hattori Y, Okamoto Y, Nagatsuka K, Takahashi R, Kalaria RN, Kinoshita M, Ihara M
    • Journal Title

      NeuroReport

      Volume: 26 Issue: 3 Pages: 113-117

    • DOI

      10.1097/wnr.0000000000000308

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Silent Information Regulator 2 Homolog 1 Counters Cerebral Hypoperfusion Injury by Deacetylating Endothelial Nitric Oxide Synthase2014

    • Author(s)
      Hattori Y, Okamoto Y, Maki T, Yamamoto Y, Oishi N, Yamahara K, Nagatsuka K, Takahashi R, Kalaria RN, Fukuyama H, Kinoshita M, Ihara M
    • Journal Title

      Stroke

      Volume: 45 Issue: 11 Pages: 3403-3411

    • DOI

      10.1161/strokeaha.114.006265

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid.2014

    • Author(s)
      Maki T, Okamoto Y, Carare RO, Hase Y, Hattori Y, Hawkes CA, Saito S, Yamamoto Y, Terasaki Y, Ishibashi-Ueda H, Taguchi A, Takahashi R, Miyakawa T, Kalaria RN, Lo EH, Arai K, Ihara M
    • Journal Title

      Ann Clin Transl Neurol

      Volume: 1 Issue: 8 Pages: 519-533

    • DOI

      10.1002/acn3.79

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Motor and cognitive impairment in a mouse model of ischemic carotid artery disease.2014

    • Author(s)
      Hattori Y, Kitamura A, Tsuji M, Nagatsuka K, Ihara M
    • Journal Title

      Neurosci Lett

      Volume: 581 Pages: 1-6

    • DOI

      10.1016/j.neulet.2014.08.009

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cilostazol add-on therapy in patients with mild dementia receiving donepezil : a retrospective study2014

    • Author(s)
      Ihara M, Nishino M, Taguchi A, Yamamoto Y, Hattori Y, Saito S, Takahashi Y, Tsuji M, Kasahara Y, Takata Y, Okada M
    • Journal Title

      PloS ONE

      Volume: 9(2) Issue: 2 Pages: e89516-e89516

    • DOI

      10.1371/journal.pone.0089516

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effects of intravenous administration of umbilical cord blood CD34+ cells in a mouse model of neonatal stroke.2014

    • Author(s)
      Tsuji M, Taguchi A, Ohshima M, Kasahara Y, Sato Y, Tsuda H, Otani K, Yamahara K, Ihara M, Harada-Shiba M, Ikeda T, Matsuyama T.
    • Journal Title

      Neuroscience

      Volume: 263 Pages: 148-158

    • DOI

      10.1016/j.neuroscience.2014.01.018

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] A mouse model of chronic cerebral hypoperfusion characterizing features of cognitive impairment2014

    • Author(s)
      Ihara M, Taguchi A, Maki T, Washida K, Tomimoto H
    • Journal Title

      Methods Mol Biol

      Volume: 1135 Pages: 95-102

    • DOI

      10.1007/978-1-4939-0320-7_8

    • ISBN
      9781493903191, 9781493903207
    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] 高血糖とアルツハイマー病.2014

    • Author(s)
      猪原匡史
    • Journal Title

      医学のあゆみ

      Volume: 249 Pages: 545-550

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] 注目される脳小血管病による認知症.2014

    • Author(s)
      猪原匡史
    • Journal Title

      Dementia Japan

      Volume: 28 Pages: 57-67

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] White matter pathology and disconnection in the frontal lobe in CADASIL2013

    • Author(s)
      Craggs LJL, Yamamoto Y, et al.
    • Journal Title

      Neuropathol Appl Neurobiol

      Volume: (Epub ahead of orint) Issue: 5 Pages: 591-602

    • DOI

      10.1111/nan.12073

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Vascular and neurodegenerative pathways-will they meet?2013

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

      Nat Rev Neurol

      Volume: 9(9) Issue: 9 Pages: 487-488

    • DOI

      10.1038/nrneurol.2013.164

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of Novel (123)I-Labeled Pyridyl Benzofuran Derivatives for SPECT Imaging of β-Amyloid Plaques in Alzheimer's Disease.2013

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

      PLoS One

      Volume: 8 Issue: 9 Pages: e74104-e74104

    • DOI

      10.1371/journal.pone.0074104

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Structure-activity Relationships and in vivo Evaluation of Quinoxaline Derivatives for PET Imaging of β-Amyloid Plaques.2013

    • Author(s)
      Yoshimura M, Ono M, Matsumura K, Watanabe H, Kimura H, Cui M, Nakamoto Y, Togashi K, Okamoto Y, Ihara M, Takahashi R, Saji H.
    • Journal Title

      ACS Med Chem Lett

      Volume: 4 Issue: 7 Pages: 596-600

    • DOI

      10.1021/ml4000707

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cilostazol improves cognitive function in patients with mild cognitive impairment : A retrospective analysis2013

    • Author(s)
      Taguchi A, Takata Y, Ihara M, Kasahara Y, Tsuji M, Nishino M, Stern D, Okada M
    • Journal Title

      Psychogeriatrics

      Volume: 13(3) Issue: 3 Pages: 164-169

    • DOI

      10.1111/psyg.12021

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Experimental and clinical challenge for neuroregeneration following stroke.2013

    • Author(s)
      Kasahara Y, Ihara M, Taguchi A.
    • Journal Title

      Front Neurol Neurosci

      Volume: 32 Pages: 69-75

    • DOI

      10.1159/000346416

    • ISBN
      9783318023084, 9783318023091
    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] An highly reproducible model of cerebralischemia/reperfusion with extended survival in CB-17 mice2013

    • Author(s)
      Kasahara Y, Ihara M, Nakagomi T, Momota Y, Sterm D, Matsuyama T, Taguchi A
    • Journal Title

      Neurosci Res

      Volume: 76 Issue: 3 Pages: 163-168

    • DOI

      10.1016/j.neures.2013.04.001

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Association of Physical Activity with the Visuospatial/Executive Functions of the Montreal Cognitive Assessment in Patients with Vascular Cognitive Impairment2013

    • Author(s)
      Ihara M, Okamoto Y, Hase Y, Takahashi R
    • Journal Title

      J Stroke Cerebrovasc Dis

      Volume: 22(7) Issue: 7 Pages: 339-4

    • DOI

      10.1016/j.jstrokecerebrovasdis.2012.10.007

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Vascular Risk Factors and Neurodegeneration in Ageing related Dementias : Alzheimer' s Disease and Vascular Dementia2013

    • Author(s)
      Akinyemi R, Mukaetova-Ladinska E, Attems J, Ihara M, Kalaria RN
    • Journal Title

      Curr Alzheimer Res

      Volume: 10(6) Issue: 6 Pages: 642-53

    • DOI

      10.2174/15672050113109990037

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Synthesis and biological evaluation of novel styryl benzimidazole derivatives as probes for imaging of neurofibrillary tangles in Alzheimer's disease.2013

    • Author(s)
      Matsumura K, Ono M, Yoshimura M, Kimura H, Watanabe H, Okamoto Y, Ihara M, Takahashi R, Saji H.
    • Journal Title

      Bioorg Med Chem

      Volume: 21 Issue: 11 Pages: 3356-3362

    • DOI

      10.1016/j.bmc.2013.02.054

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Visualization of Lenticulostriate Arteries by Flow-Sensitive Black-Blood MR Angiography on a 1.5T MRI System: A Comparative Study between Subjects with and without Stroke. AJNR Am J Neuroradiol.2013

    • Author(s)
      Okuchi S
    • Journal Title

      AJNR Am J Neuroradiol

      Volume: 34 Issue: 4 Pages: 780-784

    • DOI

      10.3174/ajnr.a3310

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Greater suitability of the Montreal Cognitive Assessment against the Mini-Mental State Examination in the detection of vascular cognitive impairment2013

    • Author(s)
      Ihara M, Okamoto Y, Takahashi R
    • Journal Title

      J Stroke Cerebrovasc Dis

      Volume: 22(6) Issue: 6 Pages: 737-41

    • DOI

      10.1016/j.jstrokecerebrovasdis.2012.01.001

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] 認知症における血管病の重要性.2013

    • Author(s)
      猪原匡史
    • Journal Title

      脳循環代謝

      Volume: 24 Pages: 83-88

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] 認知症の診断と治療を目指した小血管病の管理2013

    • Author(s)
      猪原匡史
    • Journal Title

      Brain and Nerve

      Volume: 65 Pages: 801-809

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] 「長寿遺伝子」SIRT1はeNOSを脱アセチル化することで脳低灌流侵襲に対する抵抗性を賦与する2015

    • Author(s)
      猪原匡史
    • Organizer
      脳卒中学会
    • Place of Presentation
      広島
    • Year and Date
      2015-03-26 – 2015-03-29
    • Related Report
      2014 Annual Research Report
  • [Presentation] Bench to bedside: using mouse models to identify new treatment approaches for Alzheimer’s disease.

    • Author(s)
      Masafumi Ihara.
    • Organizer
      Invited lecture: 19th Southampton Neuroscience Group (SoNG) Meeting
    • Place of Presentation
      Southampton
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] Generating rodent models of chronic cerebral hypoperfusion and investigating the pathogenesis of vascular cognitive impairment.

    • Author(s)
      Masafumi Ihara.
    • Organizer
      Plenary session (Special session on animal models of VCI). Vas-Cog2013
    • Place of Presentation
      Toronto
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] Lessons from rodent models characterizing features of vascular cognitive impairment.

    • Author(s)
      Masafumi Ihara.
    • Organizer
      Minisymposium (Animal models of VCI). Vas-Cog2013
    • Place of Presentation
      Toronto
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] シンポジウム5「血管性認知障害」血管性認知障害の病態-モデル動物を用いて明らかとなった知見-

    • Author(s)
      猪原匡史
    • Organizer
      第39回日本脳卒中学会総会
    • Place of Presentation
      大阪
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] 「認知症の発症にかかわる脳血管の機能」.

    • Author(s)
      猪原匡史
    • Organizer
      脳心血管抗加齢研究会2013
    • Place of Presentation
      大阪
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] シロスタゾールによる血管依存性βアミロイドクリアランスの促進.

    • Author(s)
      猪原匡史
    • Organizer
      脳循環代謝学会
    • Place of Presentation
      札幌
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] 「血管病としての認知症」

    • Author(s)
      猪原匡史
    • Organizer
      Vas-Cog Japan
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Presentation] S2-5-2中枢神経疾患治療に対するトランスレーショナルリサーチの現状とその課題.

    • Author(s)
      Masafumi Ihara.
    • Organizer
      Novel mechanism and therapy to treat patient with dementia. Neuro2013
    • Place of Presentation
      京都
    • Related Report
      2013 Research-status Report
  • [Presentation] Symposium S(4)-1.Vascular Dementia and Its Associated Conditions-Vascular Cognitive Impairment (VCI).Cerebral amyloid angiopathy and cognitive impairment.

    • Author(s)
      Masafumi Ihara.
    • Organizer
      第54回日本神経学会学術大会
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Remarks] 国立循環器病研究センター病院・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
      2014 Annual Research Report

URL: 

Published: 2014-07-25   Modified: 2019-07-29  

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