The molecular mechanism for Aβ oligomer hypothesis in Alzheimer's disease

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390271
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka City University
• Principal Investigator: MORI Hiroshi 大阪市立大学, 大学院・医学研究科, 教授 (10159189)
• Co-Investigator(Kenkyū-buntansha): MATSUYAMA Syogo 姫路獨協大学, 薬学部, 教授 (80243319) ; ISO Hiroyuki 神戸医療大学, 共通教育センター, 教授 (80068585)
• Project Period (FY): 2009 – 2011
• Keywords: アミロイド / 遺伝変異 / モデルマウス / 認知症

Research Abstract

We here provided in vivo and in vitro evidence to support Aβ oligomer hypothesis that is widely believed to be the most reliable idea to understand Alzheimer's disease. To verify its certification, we examined not only patients with familial AD by clinical and brain imaging analyses but also a new mouse model bearing solely Aβ oligomer. We found the abnormal accumulation of intraneuronal Aβ oligomer as a beginning pathological change. Thus more concern must be concentrated on Aβ oligomer to develop its measurement for the precise diagnosis and the treatment for the proper medication.

Research Products

• [Journal Article] Hypercholessterolemia accelerates intraneuronnal accumulaation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice (2012)
  • Author(s): Umeda T, Toomiyama T, Kitajima E, Idomoto T, Nomura S, Lambert M. P, Klein W. L & Mori H
  • Journal Title: Life Sciencee Volume: (in press)
  • Peer Reviewed
• [Journal Article] Cliniical Course of Patients with Familial Early-Onset Alzheimer's Disease Potentially Lacking Senile Plaques Bearing the E693delta Mutation in Amyloid Precursor Protein (2011)
  • Author(s): Shimada H, Ataka S, Toomiyama T, Takeuchi H, Mori H, & Miki T
  • Journal Title: Dement Geriatr Cogn Disord Volume: 32 Pages: 45-54
  • Peer Reviewed
• [Journal Article] Pittsburgh Compound B-Negative Dementia-A Possibility of Misdiagnosis of Patients With Non-Alzheimer Disease-Type Dementia as Having AD (2011)
  • Author(s): Shimada H, Ataka S, Takeuchi J, Mori H, Wada Y, Watanabe Y, & Miki T
  • Journal Title: Journal of Geriatric Psychiatry and Neurology Volume: 24 Pages: 123-126
  • Peer Reviewed
• [Journal Article] Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo (2011)
  • Author(s): Umeda T, Tomiyama T, Sakama N, Tanaka S, Lambert MP, L. Klein W, & Mori H
  • Journal Title: Journal of Neuroscience Research Volume: 89 Pages: 1031-1042
  • Peer Reviewed
• [Journal Article] In vivo positron emission tomographic imaging of glial responses to amyloid-βand tau paathologies in mouse models of Alzheimer's disease and related disorders (2011)
  • Author(s): Maeda J, M-R Zhang, Okauchi T, Bin Ji, Ono M, Hattori H, Kumata K, Iwata N, Saido T, Trojanowski J, Lee V, Staufenbiel M, Tomiyama T, Mori H, Fukumura T, Suhara T, & Higuchi M
  • Journal Title: Journal of Neuroscience Volume: 31(12) Pages: 4720-4730
  • Peer Reviewed
• [Journal Article] E22delta Mutation in amyloid beta-protein promotes beta-sheet transformation, radical production, and synaptotoxicity, but not neurotoxicity (2011)
  • Author(s): Suzuki T, Murakami K, Izuo N, Kume T, Akaike A, Nagata T, Nishizaki T, Tomiyama T, Takuma T, Mori H, Irie K
  • Journal Title: Internattional Journal of Alzheimers Disease Pages: 431320-431327
  • Peer Reviewed
• [Journal Article] Oligomeric Aβis the sole culprit molecule to cause Alzheimer's disease (2010)
  • Author(s): Mori H, Tomiyama T, Ishibashi K, Ohnishi K, Teraoka R, Fukushima A, Takuma H, Shimada H, Ataka S, Umeda T, Kitajima E, Fujita Y, Yamashita Y, Yamamoto K, Miki T, Matsuyama S, Iso H, Nagata T, Nishizaki T, Wada Y, Yoshioka E, Watanabe Y
  • Journal Title: Hirosaki Med Journal Volume: 61 Pages: 105-110
  • Peer Reviewed
• [Journal Article] Regulation of cholesterol efflux by amyloidβsecretion (2010)
  • Author(s): Umeda T, Mori H, Zheng H, Tomiyama T
  • Journal Title: Journal of Neuroscience Research Volume: 88 Pages: 1985-1994
  • Peer Reviewed
• [Journal Article] A mouse model of amyloidβoligomers : Their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo (2010)
  • Author(s): Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma T, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T, Nishitsuji K, ItoK, Shimada H, Mary Lambert, William Klein & Mori H
  • Journal Title: Journal of Neuroscience Volume: 30 Pages: 4845-4856
  • Peer Reviewed
• [Journal Article] DCP-LA neutralizes mutant amyloidβpeptide-induced impairment of long-term potentiation and spatial learning (2010)
  • Author(s): Nagata T, Tomiyama T, Mori H, Yaguchi T & Nishizaki T
  • Journal Title: Behavioural Brain Research Volume: 206 Pages: 151-154
  • Peer Reviewed
• [Journal Article] High striatal amyloidβ-Peptide deposition across different autosomal Alzheimer disease mutation types (2009)
  • Author(s): Villemagne V. L, Ataka S, Mizuno T, Brooks W. S, Wada Y, Kondo M, Jones G, Watanabe Y, Mulligan R, Nakagawa M, Miki T, Shimada H, O Keefe G. J, Masters C. L, Mori H & Rowe C. C
  • Journal Title: Archives of neurology Volume: 66 Pages: 1537-1544
  • Peer Reviewed
• [Journal Article] The E693Delta mutation in amyloid precursor protein increases intracellular accumulation of amyloid beta oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells (2009)
  • Author(s): Nishitsuji K, Tomiyama T, Ishibashi K, Ito K, Teraoka R, Lambert MP, Klein WL & Mori H
  • Journal Title: The American journal of pathology Volume: 174 Pages: 957-969
  • Peer Reviewed
• [Journal Article] Oligomeric amyloid beta-protein as a therapeutic target in Alzheimer's disease : its significance based on its distinct localization and the occurrence of a familial variant form (2009)
  • Author(s): Ito K, Ishibashi K, Tomiyama T, Umeda T, Yamamoto K, Kitajima E, Idomoto T, Nagatomo T & Mori H
  • Journal Title: Current Alzheimer research Volume: 6 Pages: 132-136
  • Peer Reviewed
• [Presentation] Perspective on the role of oligomer in Alzheimer's disease (2011)
  • Author(s): Hiroshi Mori
  • Organizer: International Conference on Alzheimer's disease(AAICAD) 2011
  • Place of Presentation: Paris, France
  • Year and Date: 20110716-21
• [Presentation] Intraneuronal amyloidβoligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo (2011)
  • Author(s): Tomohiro Umeda
  • Organizer: International Conference on Alzheimer's disease(AAICA) 2011
  • Place of Presentation: Paris, France
  • Year and Date: 20110716-21
• [Presentation] The E693 delta mutation in amyloid precursor protein impairs Aβ-mediated cholesterol efflux from cells, leading to accelerated accumulation of Intraneuronal Aβ oligomers and memory disturbance in mice with hypercholesterolemia (2011)
  • Author(s): Sachiko Nomura
  • Organizer: Neuroscience 2011
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2011-11-14
• [Presentation] The E693Δmutation in amyloid precursor protein impairs Aβ-mediated cholesterol efflux from cells in vitro (2011)
  • Author(s): 梅田知宙
  • Organizer: 第30回日本認知症学会
  • Place of Presentation: タワーホール船堀(東京都)
  • Year and Date: 2011-11-13
• [Presentation] Intracellular Aβ oligomers cause cell death via ER stress, lysosomal leakage, and mitochondrial dysfunction in cultured cells (2010)
  • Author(s): 富山貴美
  • Organizer: 第29回日本認知症学会
  • Place of Presentation: ウィンクあいち(愛知県)
  • Year and Date: 20101105-07
• [Presentation] Subcellular localization and toxicity of intracellular Aυoligomers in APP transgenic mice with the E693△(Osaka) mutation (2010)
  • Author(s): 梅田知宙
  • Organizer: 第29回日本認知症学会
  • Place of Presentation: ウィンクあいち(愛知県)
  • Year and Date: 20101105-07
• [Presentation] Intraneuronal accumulation of Aβ oligomers causes abnormal tau phosphorylation, glial activation, and neuronal loss in transgenic mice with APP E693Δmutation (2010)
  • Author(s): Takami Tomiyama
  • Organizer: International Conference on Alzheimer's Disease(ICAD)
  • Place of Presentation: ハワイコンベンションセンター(米国ホノルル)
  • Year and Date: 20100710-15
• [Presentation] Regulation of cholesterol efflux by amyloidβsecretion (2010)
  • Author(s): Tomohiro Umeda
  • Organizer: International Conference on Alzheimer's Disease(ICAD)
  • Place of Presentation: ハワイコンベンションセンター(米国ホノルル)
  • Year and Date: 20100710-15
• [Presentation] Hypercholesterolemia accelerates memory impairment in a transgenic mouse model of Aβ oligomers (2010)
  • Author(s): Erika Kitajima
  • Organizer: International Conference on Alzheimer's Disease(ICAD)
  • Place of Presentation: ハワイコンベンションセンター(米国ホノルル)
  • Year and Date: 20100710-15
• [Presentation] アルツハイマー型認知症の根本治療薬開発の現状と展望 (2010)
  • Author(s): 森啓
  • Organizer: 第一回認知症ケア学会・中国四国地方会
  • Place of Presentation: 米子コンベンションセンター(鳥取)
  • Year and Date: 2010-12-05
• [Presentation] Aβmonomer, oligomer and fibril in Alzheimer's disease The International (2009)
  • Author(s): Hiroshi Mori
  • Organizer: Symposium on Early Detection and Rehabilitation Technology of Dementia
  • Place of Presentation: Okayama Univ
  • Year and Date: 20091211-12
• [Presentation] A transgenic mouse model of amyloidβoligomers (2009)
  • Author(s): 富山貴美
  • Organizer: 第28回日本認知症学会学術集会
  • Place of Presentation: 東北大学百周年記念会館・艮陵会館
  • Year and Date: 20091119-22
• [Presentation] Regulation of cholesterol efflux by amyloid b secretion(Aβ分泌によるコレステロールeffluxの制御) (2009)
  • Author(s): 梅田知宙
  • Organizer: 第28回日本認知症学会学術集会
  • Place of Presentation: 東北大学百周年記念会館・艮陵会館
  • Year and Date: 20091119-22
• [Presentation] 高齢ホッキョクグマの脳神経病理学的剖検報告 (2009)
  • Author(s): 藤田有紀
  • Organizer: 第28回日本認知症学会学術集会
  • Place of Presentation: 東北大学百周年記念会館・艮陵会館
  • Year and Date: 20091119-22
• [Presentation] Homozygous APP mutations and Alzheimer's disease (2009)
  • Author(s): Hiroshi Mori
  • Organizer: 12th International Conference on Alzheimer's Disease(ICAD)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20090711-16
• [Presentation] A transgenic mouse model of amyloidυoligomers : Pathological effects of the E693△mutation in amyloid precursor protein in vivo (2009)
  • Author(s): Tomiyama Takami
  • Organizer: 12th International Conference on Alzheimer's Disease(ICAD)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20090711-16
• [Presentation] 老人斑を越えて (2009)
  • Author(s): 森啓
  • Organizer: 第24回日本老年精神医学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20090619-20
• [Presentation] Beyond amyloid b fibrils (2009)
  • Author(s): Hiroshi Mori
  • Organizer: Wenner-Gren Foundations International Symposium "Alzheimer therapy : still a challenge" Wenner Gren Center
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 20090506-09
• [Presentation] アルツハイマー病はアミロイドが原因でおこる (2009)
  • Author(s): 森啓
  • Organizer: 日本女性薬剤師会
  • Place of Presentation: 星薬科大学メインホール
  • Year and Date: 2009-06-21
• [Remarks]
  • URL: http://www.med.osaka-cu.ac.jp/Neurosci/