Establishment and application of novel type of Alzheimer's disease model mouse

• Project/Area Number: 23680039
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: SAITO Takashi 独立行政法人理化学研究所, 脳科学総合研究センター, 副チームリーダー (90360552)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥25,220,000 (Direct Cost: ¥19,400,000、Indirect Cost: ¥5,820,000); Fiscal Year 2013: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2012: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2011: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
• Keywords: アルツハイマー病 / モデルマウス / アミロイドβペプチド / トランスレーショナルリサーチ / アミロイド前駆体タンパク / プレセニリン1(PS1) / ノックインマウス

Research Abstract

Experimental studies of Alzheimer's disease (AD) have largely depended on transgenic (Tg) mice overexpressing amyloid precursor protein (APP). These mice, however, suffer from artificial phenotypes because not only amyloid beta peptide (Abeta) but also other APP fragments are overproduced. To overcome these drawbacks, we generated knockin mice that harbor Swedish and Iberian mutations in the APP gene, and demonstrated that these animals start accumulating Abetaat 6 months and show memory impairment at 18 months without APP overexpression.
We also generated mice containing an additional Arctic mutation; these started depositing Abeta at 2 months and showed memory impairment at 6 months with aggressive neuroinflammation. We provide the research community with these lines in order to distinguish facts from artifacts in APP-Tg mice and to identify pathological mechanisms upstream and downstream of Abeta deposition.

Research Products

• [Journal Article] Single APP knockin mouse models of Alzheimer's disease (2014)
  • Author(s): T. Saito, Y. Matsuba, N. Mihira, J. Takano, P. Nilsson, S. Itohara, N. Iwata, T.C. Saido
  • Journal Title: Nature Neuroscience Volume: 17 Issue: 5 Pages: 661-663
  • DOI: 10.1038/nn.3697
  • Peer Reviewed
• [Journal Article] Substrate ectodomain is critical for substrate preference and inhibition ofβ-secretase (2013)
  • Author(s): S. Funamoto, T. Sasaki, S. Ishihara, M. Nobuhara, M. Nakano, M. Takahashi, T. Saito, N. Kakuda, T. Miyasaka, K. Nishikawa, T.C. Saido, Y. Ihara
  • Journal Title: Nature Communications Volume: 4 Issue: 1 Pages: 1-12
  • DOI: 10.1038/ncomms3529
  • Peer Reviewed
• [Journal Article] Αβ secretion and plaque formation depend on autophagy (2013)
  • Author(s): Nilsson, P., Loganathan, K., Sekiguchi, M., Matsuba, Y., Hui, K., Tsubuki, S., Tanaka, M., Iwata, N., Saito, T., Saido, T. C.
  • Journal Title: Cell Reports Volume: 5 Issue: 1 Pages: 61-69
  • DOI: 10.1016/j.celrep.2013.08.042
  • Peer Reviewed
• [Journal Article] Human prefoldin inhibits Aβfibrillation and contributes to formation of non-toxic Aβaggregates (2013)
  • Author(s): K.M. Sörgjerd, T. Zako, M. Sakono, P.C. Stirling, M.R. Leroux, T. Saito, P. Nilsson, M. Sekimoto, T.C.Saido, M. Maeda
  • Journal Title: Biochemistry Volume: 52 Issue: 20 Pages: 3532-3542
  • DOI: 10.1021/bi301705c
  • Peer Reviewed
• [Journal Article] Cell surface expression of the major amyloid-β peptide (Aβ)-degrading enzyme, neprilysin, depends on phosphorylation by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and dephosphorylation by protein phosphatase 1a. (2012)
  • Author(s): Kakiya, Naomasa
  • Journal Title: J.Biol.Chem. Volume: 287 Issue: 35 Pages: 29362-29572
  • DOI: 10.1074/jbc.m112.340372
  • Peer Reviewed
• [Journal Article] Potent amyloidogenicity and pathogenicity of Aβ43 (2011)
  • Author(s): Takashi Saito, Takahiro Suemoto, Nathalie Brouwers, Kristel Sleegers, Satoru Funamoto, Naomi Mihira, Yukio Matsuba, Kazuyuki Yamada, Per Nilsson, Jiro Takano, Masaki Nishimura, Nobuhisa Iwata, Christine Van Broeckhoven, Yasuo Ihara, Takaomi C Saido
  • Journal Title: Nature Neuroscience Volume: 14 Issue: 8 Pages: 1023-1032
  • DOI: 10.1038/nn.2858
  • NAID: 120006985066
  • Peer Reviewed
• [Presentation] 新規アルツハイマー病モデルマウスの作製と応用 (2014)
  • Author(s): 斉藤貴志、松葉由紀夫、三平尚美、西道隆臣
  • Organizer: 日本薬学会
  • Place of Presentation: (熊本)(シンポジウム講演)
  • Year and Date: 2014-03-29
• [Presentation] Identification of intracellular signal pathway of somatostatin-induced neprilysin activity (2013)
  • Author(s): N. Kakiya, T. Saito, P. Nilsson, L. Auboyer, M. Madison and T.C. Saido
  • Organizer: Society for Neuroscience 2013
  • Place of Presentation: (SanDiego, USA) .(ポスター発表)
  • Year and Date: 2013-11-12
• [Presentation] Update of novel type and more relevant model mouse for Alzheimer's disease (2013)
  • Author(s): T. Saito, Y. Matsuba, N. Mihira, N. Iwata, J. Takano, P. Nilsson and T.C. Saido
  • Organizer: Alzheimer Association of International Conference2013
  • Place of Presentation: (Boston, USA) (口頭発表)
  • Year and Date: 2013-07-15
• [Presentation] アルツハイマー病の治療・予防・診断法の確立を目指して (2013)
  • Author(s): 斉藤貴志
  • Organizer: 日本生化学会関東支部例会
  • Place of Presentation: (甲府、山梨県)
  • Year and Date: 2013-06-15
  • Invited
• [Presentation] The role of intracellular domain in neprilysin for the metabolic pathway and enzymatic activity of nepriylsin (2012)
  • Author(s): 垣矢直雅、斉藤貴志、Per Nilsson、松葉由紀夫、津吹聡、西道隆臣
  • Organizer: 日本生化学会
  • Place of Presentation: (福岡)(ポスター発表)
  • Year and Date: 2012-12-15
• [Presentation] アミロイドβ43によるアルツハイマー病の病態発症・促進機構に関する研究 (2012)
  • Author(s): 斉藤貴志
  • Organizer: 日本生化学会
  • Place of Presentation: (福岡)(日本生化学会奨励賞受賞講演)
  • Year and Date: 2012-12-14
• [Presentation] 新規APPノックインマウスの作製と応用 (2012)
  • Author(s): 斉藤貴志、松葉由紀夫、三平尚美、岩田修永、高野二郎、Per Nilsson、西道隆臣
  • Organizer: 日本認知症学会
  • Place of Presentation: (つくば、茨城県)(口頭発表)
  • Year and Date: 2012-10-26
• [Presentation] Novel type and more relevant model mouse for Alzheimer's disease (2012)
  • Author(s): T. Saito, Y. Matsuba, N. Mihira, N. Iwata, J. Takano, P. Nilsson and T.C. Saido
  • Organizer: Society for Nueroscience 2012
  • Place of Presentation: (New Orleans, USA) (ポスター発表)
  • Year and Date: 2012-10-15
• [Presentation] APP knock-in mouse : a novel type and more relevant model mouse for Alzheimer's disease (2012)
  • Author(s): T. Saito, Y. Matsuba, N. Mihira, N. Iwata, J. Takano, P. Nilsson and T.C. Saido
  • Organizer: Alzheimer Association of International Conference2012
  • Place of Presentation: (Vancouver, Canada) (ポスター発表)
  • Year and Date: 2012-07-15
• [Presentation] Aβ43 is the potent pahological accelerator for Alzheimer's disease (2011)
  • Author(s): T. Saito, N. Mihira, Y. Matsuba and T.C. Saido
  • Organizer: Alzheimer Association of International Conference2011
  • Place of Presentation: (Paris, France) (ポスター発表)
  • Year and Date: 2011-07-18
• [Presentation] Aβ43 is the potent pathological accelerator for Alzheimer's disease (2011)
  • Author(s): Saito T., et al
  • Organizer: Alzheimer's Association International Conference 2011
  • Place of Presentation: Paris (France)
  • Year and Date: 2011-07-18
• [Presentation] 新規アルツハイマー病モデルマウスの作製と応用
  • Author(s): 斉藤貴志、松葉由紀夫、三平尚美、西道隆臣
  • Organizer: 日本薬学会
  • Place of Presentation: 熊本県民会館（熊本県）
• [Presentation] Identification of intracellular signal pathway of somatostatin-induced neprilysin activity
  • Author(s): Kakiya N., Saito T., Nilsson P., Auboyer L., Madison M. and Saido T.C.
  • Organizer: Society for Neuroscience
  • Place of Presentation: SanDiego, USA
• [Presentation] Update of novel type and more relevant model mouse for Alzheimer’s disease
  • Author(s): Saito T, Matsuba Y, Mihira N, Iwata N, Takano J, Nilsson P and Saido TC
  • Organizer: Alzheimer Association of International Conference2013
  • Place of Presentation: Boston, USA
• [Presentation] アルツハイマー病の治療・予防・診断法の確立を目指して
  • Author(s): 斉藤貴志
  • Organizer: 日本生化学会関東支部例会
  • Place of Presentation: 山梨大学（山梨県）
  • Invited
• [Presentation] アミロイドβ43によるアルツハイマー病の病態発症・促進機構に関する研究
  • Author(s): 斉藤 貴志
  • Organizer: 日本生化学会
  • Place of Presentation: 福岡国際会議場
  • Invited
• [Presentation] The role of intracellular domain in neprilysin for the metabolic pathway and enzymatic activity of neprilysin
  • Author(s): 垣矢直雅、斉藤貴志、Per Nilsson、松葉由紀夫、津吹聡、西道隆臣
  • Organizer: 日本生化学会
  • Place of Presentation: 福岡国際会議場
• [Presentation] 新規APPノックインマウスの作製と応用
  • Author(s): 斉藤 貴志、松葉 由紀夫、三平 尚美、岩田 修永、高野 二郎、Per Nilsson、西道 隆臣
  • Organizer: 日本認知症学会学術集会
  • Place of Presentation: つくば国際会議場
• [Presentation] Novel type and more relevant model mouse for Alzheimer’s disease
  • Author(s): Takashi Saito, Yukio Matsuba, Naomi Mihira, Nobuhisa Iwata, Jiro Takano, Per Nilsson and Takaomi C. Saido
  • Organizer: Annual meeting of Society for Neuroscience 2012
  • Place of Presentation: ニューオリンズ（アメリカ）
• [Presentation] APP knock-in mouse: a novel and more relevant model mouse for Alzheimer’s disease
  • Author(s): Takashi Saito, Yukio Matsuba, Naomi Mihira, Nobuhisa Iwata, Jiro Takano, Per Nilsson and Takaomi C. Saido
  • Organizer: Alzheimer’s Association International Conference 2012
  • Place of Presentation: バンクーバー（カナダ）
• [Remarks] 平成25年度 文部科学大臣表彰 若手科学者賞 <受賞>
• [Remarks] 平成24年度 日本生化学会奨励賞 <受賞>
• [Remarks] 発表論文①のプレスリリースを行った。
  • URL: http://www.riken.jp/pr/press/2014/20140414_1/
• [Remarks] 発表論文⑥のプレスリリースを行った。 <プレスリリース>
  • URL: http://www.riken.jp/r-world/info/release/press/2011/110704/detail.html
• [Remarks] 理研一般公開2013(2013年4月20日) <アウトリーチ活動>
• [Remarks] 理研一般公開2012(2012年4月21日) <アウトリーチ活動>
• [Remarks] 理研一般公開2011(2011年4月16日) <アウトリーチ活動>
• [Remarks] 文部科学大臣表彰について
  • URL: http://www.riken.jp/pr/topics/2013/20130416_1/
• [Remarks] 上記発表論文に関するプレスリリースを行った。
  • URL: http://www.riken.jp/r-world/info/release/press/2011/110704/detail.html