血管からみたアルツハイマー病の新規治療法の開発

2012 年度 研究成果報告書

• 研究課題/領域番号: 22390145
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 内科学一般(含心身医学)
• 研究機関: 大阪大学
• 研究代表者: 森下 竜一 大阪大学, 医学系研究科, 教授 (40291439)
• 研究分担者: 島村 宗尚 大阪大学, その他研究科, 准教授 (60422317) ; 里 直行 大阪大学, 医学系研究科, 准教授 (70372612) ; 内藤 こずえ 独立行政法人医薬基盤研究所, その他部局等 (70373397)
• 研究期間 (年度): 2010 – 2012
• キーワード: ベータ・アミロイド / 炎症 / 血液脳関門 / サイトカイン

研究概要

超高齢化社会を迎える現代社会にとって、アルツハイマー病(AD)は解決の待たれる疾患である。近年、血管因子が注目されており、血管からみたAD新規治療薬の探索を行った。我々はADモデル動物において血管に炎症を惹起するとその炎症の脳内への波及が増強することを見出し、その原因として血液脳関門の破綻を示した。血液脳関門の破綻を抑止することがADの予防・治療ターゲットになりうることを提示した。

研究成果

• [雑誌論文] Increased Blood-Brain Barrier Vulnerability to Systemic Inflammation in Alzheimer Disease Mouse Model. (2013)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Kazuko Ikimura, Hirohito Nishino, Hiromi Rakugi and Ryuichi Morishita
  • 雑誌名: Neurobiology of Aging 巻: (in press)
• [雑誌論文] Oral Glucose Loading Modulates Plasma Aβ Level in Alzheimer Disease Patients: Potential Diagnostic Method for Alzheimer Disease. (2012)
  • 著者名/発表者名: ShukoTakeda, Naoyuki Sato*, Kozue Uchio-Yamada, Hisahiro Yu, Atsushi Moriguchi, Hiromi Rakugi, and Ryuichi Morishita
  • 雑誌名: Dementia and Geriatric Cognitive Disorders 巻: (in press)
• [雑誌論文] Novel microdialysis method to assess neuropeptides and large molecules in free-moving mouse. (2011)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato*, Kazuko Ikimura, Hirohito Nishino, Hiromi Rakugi and Ryuichi Morishita
  • 雑誌名: Neuroscience 巻: 186 ページ: 110-9
• [雑誌論文] Role of insulin signaling in the interaction between Alzheimer disease and diabetes mellitus: a missing link to therapeutic potential. (2011)
  • 著者名/発表者名: Naoyuki Sato, Shuko Takeda, Kozue Uchio-Yamada, Hironori Ueda, Tomomi Fujisawa, Hiromi Rakugi, Ryuichi Morishita
  • 雑誌名: Current Aging Science 巻: 4 ページ: 118-127
• [雑誌論文] Reduction of brain A. by fluvastatin, an HMG-CoA reductase inhibitor, through increase in degradation of APP-CTFs and A. clearance. (2010)
  • 著者名/発表者名: Mitsuru Shinohara, Naoyuki Sato, Hitomi Kurinami, Daisuke Takeuchi, Shuko Takeda, Munehisa Shimamura, Toshihide Yamashita, Yasuo Uchiyama, Hiromi Rakugi, and Ryuichi Morishita
  • 雑誌名: The Journal of Biological Chemistry 巻: 285 ページ: 22091-22102
• [雑誌論文] Plasma Beta-Amyloid as Potential Biomarker of Alzheimer Disease: Possibility of Diagnostic Tool of Alzheimer Disease. (2010)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Hiromi Rakugi, and Ryuichi Morishita
  • 雑誌名: Molecular BioSystems 巻: 6 ページ: 1760-1766
• [雑誌論文] Diabetes accelerated memory dysfunction via cerebrovascular inflammation and A. deposition in an Alzheimer mouse model with diabetes. (2010)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Kozue Uchio-Yamada, Kyoko Sawada, Takanori Kunieda, Daisuke Takeuchi, Hitomi Kurinami, Mitsuru Shinohara, Hiromi Rakugi, and Ryuichi Morishita
  • 雑誌名: Proc Natl Acad Sci USA 巻: 13, 107 ページ: 7036-41
• [雑誌論文] Animal Models of Alzheimer Disease for Translational Research: Current and Future Concepts. Horizons in Neuroscience Research. Volume 4 (Hardcover) (2010)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Hiromi Rakugi, Ryuichi Morishita
  • 雑誌名: Nova Science Publishers
• [雑誌論文] Differential Regulation of Amyloid Precursor Protein /Presenilin 1 Interaction during Aβ40/42 Production Detected Using Fusion Constructs.
  • 著者名/発表者名: Naoyuki Sato, Masayasu Okochi, Mitsuru Shinohara, Gopal Thinakaran, Shuko Takeda, Akio Fukumori, Motoko Shinohara-Noma, Mari Mori-Ueda, Hizuki Hamada, Masatoshi Takeda, Hiromi Rakugi, Ryuichi Morishita
  • 雑誌名: PLoS ONE 巻: 7(11) ページ: e48551
• [学会発表] Role of adult common desease in the development of Alzheimer disease: Application to diagnostic and therapeutic indication (2013)
  • 著者名/発表者名: Naoyuki Sato, Ryuichi Morishita
  • 学会等名: 24th Biennial Joint Meeting
  • 発表場所: Cancun, Mexico
  • 年月日: 2013-04-22
• [学会発表] Diabetes increases tau phosphorylation in APP mice: evidence that Abeta is prerequisite, but insufficient to cause tau phosphorylation (2013)
  • 著者名/発表者名: N Sato, M Mori-Ueda, T Tanaka, S Takeda, K Uchio-Yamada, H Ueda, M Shinohara, S Murayama, M Takeda, H Rakugi, R Morishita
  • 学会等名: The 11th International Conference on Alzheimer's & Parkinson's Diseases AD/PD 2013
  • 発表場所: Italy
  • 年月日: 2013-03-10
• [学会発表] Amyloid precursor protein/presenilin 1 interaction is differentially regulated during Abeta40/42 production: detection using fusion constructs (2013)
  • 著者名/発表者名: N Sato, M Okochi, M Shinohara, G Thinakaran, S Takeda, A Fukumori, M Shinohara-Noma, M Mori-Ueda, H Hamada, M Takeda, H Rakugi, R Morishita
  • 学会等名: The 11th International Conference on Alzheimer's & Parkinson's Diseases AD/PD 2013
  • 発表場所: Italy
  • 年月日: 2013-03-09
• [学会発表] Roles of beta-amyloid and insulin resistance in the interaction between diabetes mellitus and Alzheimer's disease (2012)
  • 著者名/発表者名: Naoyuki Sato, Mari Mori-Ueda, Toshihisa Tanaka, Shuko Takeda, Kozue Uchio-Yamada, Hironori Ueda, Mitsuru Shinohara, Shigeo Murayama, Masatoshi Takeda, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: Gordon Research Conferences, Neurobiology of Brain Disorders
  • 発表場所: Stonehill College
  • 年月日: 20120805-10
• [学会発表] The mechanisms by which diabetes mellitus increases the risk of Alzheimer's disease (2012)
  • 著者名/発表者名: Naoyuki Sato, Mari Mori-Ueda, Toshihisa Tanaka, Shuko Takeda, Kozue Uchio-Yamada, Hironori Ueda, Mitsuru Shinohara, Shigeo Murayama, Masatoshi Takeda, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: Keystone Symposia, Aging and Diseases of Aging
  • 発表場所: Tokyo
  • 年月日: 2012-10-25
• [学会発表] Old APPxob/ob mice showed highly increased level of tau phosphorylation in brain (2012)
  • 著者名/発表者名: Naoyuki Sato, Mari Mori-Ueda, Toshihisa Tanaka, Shuko Takeda, Kozue Uchio-Yamada, Hironori Ueda, Mitsuru Shinohara, Shigeo Murayama, Masatoshi Takeda, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: Neuroscience 2012
  • 発表場所: New Orleans
  • 年月日: 2012-10-15
• [学会発表] Statins up-regulate APP-CTF degradation and Abeta clearance (2012)
  • 著者名/発表者名: Naoyuki Sato, Mitsuru Shinohara, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: KEYSTONE SYMPOSIA- ApoE, Alzheimer's and Lipoprotein Biology
  • 発表場所: Keystone, Colorado
  • 年月日: 2012-02-28
• [学会発表] PATHOLOGICAL INTERACTION BETWEEN ALZHEIMER DISEASE AND DIABETES MELLITUS (2011)
  • 著者名/発表者名: Naoyuki Sato, Shuko Takeda, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: Present and Future Alzheimer's Research / Grobal Alzheimer's Research Summit
  • 発表場所: Madrid
  • 年月日: 20110922-23
• [学会発表] CHANGE IN PLASMA BETA-AMYLOID LEVEL AFTER GLUCOSE LOADING : A POSSIBLE BIOMARKER FOR ALZHEIMER DISEASE (2011)
  • 著者名/発表者名: Naoyuki Sato, Shuko Takeda, Mari Ueda, Hisahiro Yu, Atsushi Moriguchi, Kozue Uchio-Yamada, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: AAIC (Alzheimer Association International Conference)2011
  • 発表場所: Paris
  • 年月日: 2011-07-18
• [学会発表] Dual Effects of a Statin on Abeta Metabolism: Up-regulation of Degradation of APP-CTF and Abeta Clearance (2011)
  • 著者名/発表者名: Naoyuki Sato, Mitsuru Shinohara, Shuko Takeda, Hiromi Rakugi, and Ryuichi Morishita
  • 学会等名: The 10th International Conference on Alzheimer's and Parkinson's Diseases (ADPD 2011)
  • 発表場所: Barcelona, Spain
  • 年月日: 2011-03-12
• [学会発表] Increased Blood-brain Barrier Vulnerability to Systemic Inflammation in Alzheimer Disease Mouse Model (2011)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Hiromi Rakugi, and Ryuichi Morishita
  • 学会等名: The 10th International Conference on Alzheimer's and Parkinson's Diseases (ADPD 2011)
  • 発表場所: Barcelona, Spain
  • 年月日: 2011-03-10
• [学会発表] Alteration in Plasma Beta-amyloid Levels after Glucose Loading Could Be a Novel Diagnostic Marker for Alzheimer Disease (2011)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Kozue Uchio-Yamada, Hisahiro Yu, Atsushi Moriguchi, Hiromi Rakugi, and Ryuichi Morishita
  • 学会等名: The 10th International Conference on Alzheimer's and Parkinson's Diseases (ADPD 2011)
  • 発表場所: Barcelona, Spain
  • 年月日: 2011-03-09
• [学会発表] Mechanistic Interaction between Alzheimer Disease and Diabetes Mellitus: Analysis of Novel Mouse Models of Alzheimer Disease with Diabetes (2011)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Kozue Uchio-Yamada, Hiromi Rakugi, and Ryuichi Morishita
  • 学会等名: The 10th International Conference on Alzheimer's and Parkinson's Diseases (ADPD 2011)
  • 発表場所: Barcelona, Spain
  • 年月日: 2011-03-09
• [学会発表] Possible Mutual Interaction Between Diabetes Mellitus and Alzheimer Disease: Generation of Novel Transgenic Mice Models of Alzheimer Disease With Diabetes (2010)
  • 著者名/発表者名: Naoyuki Sato, Shuko Takeda, Hiromi Rakugi, and Ryuichi Morishita
  • 学会等名: Microcirculation and Cerebral/Coronary/Peripheral Circulation, AHA Scientific Sessions 2010
  • 発表場所: Chicago, U.S.A.
  • 年月日: 2010-11-15
• [学会発表] Increased brain vulnerability to systemic inflammation in Alzheimer disease transgenic mouse model (2010)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Hiromi Rakugi, and Ryuichi Morishita
  • 学会等名: The 40th annual meeting of the Society for Neuroscience (Neuroscience 2010)
  • 発表場所: San Diego, U.S.A.
  • 年月日: 2010-11-15
• [学会発表] Mechanistic Interaction Between Diabetes Mellitus and Alzheimer Disease: Generation of Novel Transgenic Mouse Models of Alzheimer Disease With Diabetes (2010)
  • 著者名/発表者名: Shuko Takeda
  • 学会等名: The 4th AFLAS (Asian Federation of Laboratory Animal Science Associations) Congress Meeting
  • 発表場所: Taipei, Taiwan
  • 年月日: 2010-11-09
• [学会発表] Angiotensin Receptor Blocker Prevented β-Amyloid-Induced Memory Impairment Associated with Recovery of Neurovascular Coupling (2010)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Masanobu Kano, Toshio Ogihara, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: 23rd Scientific Meeting of the International Society of Hypertension(ISH2010)
  • 発表場所: Vancouver, Canada
  • 年月日: 2010-09-28
• [学会発表] Diabetes Accelerated Memory Dysfunction via Cerebrovascular Inflammation and Beta-Amyloid Deposition in Alzheimer Mouse Model: Generation of Novel Transgenic Mouse Models of Alzheimer Disease with Diabetes (2010)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Kozue Uchio-Yamada, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: 23rd Scientific Meeting of the International Society of Hypertension(ISH2010)
  • 発表場所: Vancouver, Canada
  • 年月日: 2010-09-27
• [学会発表] Diabetes mellitus exacerbated learning impairment via cerebrovascular inflammation and disturbance of brain insulin signaling in Alzheimer mouse models with diabetes (2010)
  • 著者名/発表者名: Shuko Takeda, Naoyuki Sato, Kozue Uchio-Yamada, Kyoko Sawada, Takanori Kunieda, Mitsuru Shinohara, Hiromi Rakugi, Ryuichi Morishita
  • 学会等名: Alzheimer's Association International Conference on Alzheimer Disease 2010(ICAD2010)
  • 発表場所: Honolulu, Hawaii
  • 年月日: 2010-07-12
• [備考]
  • URL: http://www.cgt.med.osaka-u.ac.jp/
• [備考]
  • URL: http://www.osaka-u.ac.jp/en/research/annual-report/volume-11/100_select_paper/copy6_of_science02.html
• [産業財産権] 新規マイクロダイアライシス回路を用いた脳内物質の精密測定法 (2010)
  • 発明者名: 西野博仁、生村和子、武田 朱公,里 直行,森下 竜一
  • 産業財産権番号: 特許第4625914号
  • 出願年月日: 2010-04-26