Development of a novel therapy for Alzheimer's disease based on vascular modification

2012 Fiscal Year Final Research Report

• Project/Area Number: 22390145
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General internal medicine (including Psychosomatic medicine)
• Research Institution: Osaka University
• Principal Investigator: MORISHITA Ryuichi 大阪大学, 医学系研究科, 教授 (40291439)
• Co-Investigator(Kenkyū-buntansha): SHIMAMURA Munehisa 大阪大学, その他研究科, 准教授 (60422317) ; SATO Naoyuki 大阪大学, 医学系研究科, 准教授 (70372612) ; NAITO Kozue 独立行政法人医薬基盤研究所, その他部局等 (70373397)
• Project Period (FY): 2010 – 2012
• Keywords: ベータ・アミロイド / 炎症 / 血液脳関門 / サイトカイン

Research Abstract

Development of a novel therapy for Alzheimer’s disease (AD) is needed for our society with increased elderly population. We investigated the involvement of vascular factors in the pathogenesis of AD. We found increased blood-brain barrier vulnerability to systemic inflammation in Alzheimer disease mouse model. We propose the protection of blood-brain barrier form disruption is a possible therapeutic target for AD.

Research Products

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