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

• Project/Area Number: 25640031
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: National 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: ¥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.

Research Products

• [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
  • 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
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Silent Information Regulator 2 Homolog 1 Counters Cerebral Hypoperfusion Injury by Deacetylating Endothelial Nitric Oxide Synthase (2014)
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Cilostazol add-on therapy in patients with mild dementia receiving donepezil : a retrospective study (2014)
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] A mouse model of chronic cerebral hypoperfusion characterizing features of cognitive impairment (2014)
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] White matter pathology and disconnection in the frontal lobe in CADASIL (2013)
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Cilostazol improves cognitive function in patients with mild cognitive impairment : A retrospective analysis (2013)
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] An highly reproducible model of cerebralischemia/reperfusion with extended survival in CB-17 mice (2013)
  • 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
  • Peer Reviewed
• [Journal Article] Association of Physical Activity with the Visuospatial/Executive Functions of the Montreal Cognitive Assessment in Patients with Vascular Cognitive Impairment (2013)
  • 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
  • Peer Reviewed
• [Journal Article] Vascular Risk Factors and Neurodegeneration in Ageing related Dementias : Alzheimer' s Disease and Vascular Dementia (2013)
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Greater suitability of the Montreal Cognitive Assessment against the Mini-Mental State Examination in the detection of vascular cognitive impairment (2013)
  • 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
  • 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
  • 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
  • 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
• [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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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/