Elucidation for role of intracellular/extracellulra quality control system in pathogenesis of Alzheimer's disease

• Project/Area Number: 26290019
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Saito Takashi 国立研究開発法人理化学研究所, 脳科学総合研究センター, 副チームリーダー (90360552)
• Research Collaborator: MATSUBA Yukio 理化学研究所, 神経蛋白制御研究チーム, テクニカルスタッフ ; Mihira Naomi 理化学研究所, 神経蛋白制御研究チーム, テクニカルスタッフ
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: 脳老化 / アルツハイマー病 / モデルマウス / 蛋白質代謝 / 痴呆 / 脳神経疾患 / 老化 / モデル動物

Outline of Final Research Achievements

To elucidate molecular mechanisms for pathogenesis of Alzheimer’s disease, we investigated a role of intracellular and extracellular quality control system in next generation AD mouse models, Amyloid precursor protein (APP) knockin (KI) mice, which we developed. The results taken by using existed AD mouse models which were APP overexpressing model in almost case could not be reproduced by using APP KI mice due to artifacts of APP overexpressing mouse models. Thereby, APP KI mouse models would be new world standard model for AD research community and be useful for elucidation of molecular mechanisms under pathogenesis of AD.

Research Products

• [Int'l Joint Research] Karolinska Institute(スウェーデン)
• [Int'l Joint Research] Harvard Medical School/University Pennsylvania(米国)
• [Journal Article] PLD3 gene and processing of APP (2017)
  • Author(s): P. Fazzari, K. Horre, A.M. Arranz, C.S. Frigerio, T. Saito, T.C. Saido and B. De Strooper
  • Journal Title: Nature Volume: 541 Issue: 7638 Pages: E1-E2
  • DOI: 10.1038/nature21030
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tetraspanin 6: a pivotal protein of the Multiple Vesicular Body determining exosome release and lysosomal degradation of Amyloid Precursor protein fragments. (2017)
  • Author(s): F.X. Guix, R. Sannerud, F. Berditchevski, A. Arranz, K. Horré, A. Snellinx, A. Thathiah, T. Saito, T Saido, R. Sundaresan, M. Overduin, S. Kumar-Singh, E. Radaelli, N. Corthout, J. Colombelli, S. Tosi, S. Munck, I.H. Salas,W. Annaert, B. De Strooper
  • Journal Title: Molecular Neurodegeneration Volume: 12 Issue: 1 Pages: 25-25
  • DOI: 10.1186/s13024-017-0165-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An immunoaffinity-based method for isolating ultrapure adult astrocytes based on ATP1B2 targetting by the ACSA-2 antibody. (2017)
  • Author(s): M.Y. Batiuk, F. de Vin, S.I. Duqué, C. Li, T. Saito, T.C. Saido, M. Fiers, T.G. Belgard , M.G. Holt
  • Journal Title: Journal of Biological Chemistry Volume: - Issue: 21 Pages: 8874-8891
  • DOI: 10.1074/jbc.m116.765313
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bisecting GlcNAc modification stabilizes BACE1 protein under oxidative stress conditions (2016)
  • Author(s): Kizuka Y, Nakano M, Kitazume S, Saito T, Saido TC, Taniguchi N
  • Journal Title: Biochemical Journal Volume: 473 Issue: 1 Pages: 21-30
  • DOI: 10.1042/bj20150607
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cognitive deficits in single App knock-in mouse models (2016)
  • Author(s): A. Masuda, Y. Kobayashi, N. Kogo, T. Saito, T.C. Saido and S. Itohara
  • Journal Title: Neurobiology of Learning and Memory Volume: 135 Pages: 73-82
  • DOI: 10.1016/j.nlm.2016.07.001
  • Peer Reviewed / Open Access
• [Journal Article] HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease (2016)
  • Author(s): Fujita, K., Motoki, K., Tagawa, K., Chen, X., Hama, H., Nakajima, K., Homma, H., Tamura, T., Watanabe, H., Katsuno, M., Matsumi, C., Kajikawa, M., Saito, T., Saido, T., Sobue, G., Miyawaki, A., Okazawa, H.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 31895-31895
  • DOI: 10.1038/srep31895
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Calpain activation in Alzheimer’s model mice is an artifact of APP and presenilin overexpression. (2016)
  • Author(s): T. Saito, Y. Matsuba, N. Yamazaki, S. Hashimoto and T.C. Saido
  • Journal Title: Journal of Neuroscience Volume: 36 Issue: 38 Pages: 9933-9936
  • DOI: 10.1523/jneurosci.1907-16.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ScaleS: an optical clearing palette for biological imaging. (2016)
  • Author(s): Hama H, Hioki H, Namiki K, Hoshida T, Kurokawa H, Ishidate F, Kaneko T, Akagi T, Saito T, Saido T, *Miyawaki A.
  • Journal Title: Nature Neuroscience Volume: 18 Issue: 10 Pages: 1518-1529
  • DOI: 10.1038/nn.4107
  • Peer Reviewed / Open Access
• [Journal Article] Familial Alzheimer disease mutations in presenilin generate amyloidogenic Abeta peptide seeds. (2016)
  • Author(s): S. Veugelen, T. Saito, T.C. Saido, L. Chávez-Gutiérrez, and B. De Strooper
  • Journal Title: Neuron Volume: 90 Issue: 2 Pages: 410-416
  • DOI: 10.1016/j.neuron.2016.03.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuronal store-operated calcium entry and mushroom spine loss in APP knock-in mouse model of Alzheimer’s disease. (2015)
  • Author(s): H. Zhang, L. Wu, E. Pchitskaya, O. Zaharova, T. Saito, T.C. Saido and I. Bezprozanny
  • Journal Title: Journal of Neuroscience Volume: 35 Issue: 39 Pages: 13275-13286
  • DOI: 10.1523/jneurosci.1034-15.2015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GPR3 modulation of the amyloid plaque burden and memory in Alzheimer’s disease. (2015)
  • Author(s): Y. Huang, A. Skwarek-Maruszewska, K Horré, E Vandewyer, L. Wolfs, A. Snellinx, T. Saito, E. Radaelli, N. Corthout, A. C. Lo, L. Van Aerschot, Z. Callaerts-Vegh, D. Trabzuni, K. Bossers, J. Verhaagen, M. Ryten, S. Munck, R. D’Hooge, D.F. Swaab, J. Hardy, T.C. Saido, B. De Strooper and A. Thathiah
  • Journal Title: Science Translational Medicine Volume: 7 Issue: 309
  • DOI: 10.1126/scitranslmed.aab3492
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autophagy-related protein 7 deficiency in amyloid β (Aβ) precursor protein transgenic mice decreases Aβ in the multivesicular bodies and induces Aβ accumulation in the Golgi. (2015)
  • Author(s): Nilsson P, Sekiguchi M, Akagi T, Izumi S, Komori T, Hui K, Sörgjerd K, Tanaka M, Saito T, Iwata N, Saido TC
  • Journal Title: American Journal of Pathology Volume: 185 Issue: 2 Pages: 305-313
  • DOI: 10.1016/j.ajpath.2014.10.011
  • Peer Reviewed
• [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] New mouse model of Alzheimer's (2014)
  • Author(s): Per Nilsson, Takashi Saito, Takaomi C. Saido
  • Journal Title: ACS Chemical Neuroscience Volume: 16 Issue: 7 Pages: 499-502
  • DOI: 10.1021/cn500105p
  • Open Access / Acknowledgement Compliant
• [Presentation] アルツハイマー病研究に資するモデルマウスの開発と応用 (2016)
  • Author(s): 斉藤 貴志
  • Organizer: 日本認知症学会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2016-12-01
• [Presentation] Biology of Time: Humanization of entire murine tau gene for a better model of AD (2016)
  • Author(s): Takashi Saito and Takaomi C. Saido
  • Organizer: Society for Neuroscience
  • Place of Presentation: SanDiego Convention Center
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] 次世代型アルツハイマー病モデルマウスの開発 (2016)
  • Author(s): 斉藤 貴志
  • Organizer: 第31回日本薬物動態学会年会
  • Place of Presentation: 松本キッセイ文化ホール
  • Year and Date: 2016-10-13
  • Invited
• [Presentation] アミロイドをターゲットとした認知症予防の試み (2016)
  • Author(s): 斉藤 貴志
  • Organizer: 第6回日本認知症予防学会学術集会
  • Place of Presentation: 東北大学百周年記念会館
  • Year and Date: 2016-09-24
  • Invited
• [Presentation] Somatostatin receptors regulate brain Aβ levels via the modulation of neprilysin activity (2016)
  • Author(s): Takashi Saito (Organizer), Per Nilsson, Naomasa Kakiya and Takaomi C. Saido
  • Organizer: The 39th Annual meeting of the Japan Neuroscience Society
  • Place of Presentation: 横浜国際会議場
  • Year and Date: 2016-07-20
• [Presentation] アルツハイマー病における神経炎症制御 (2015)
  • Author(s): 斉藤貴志
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-04
• [Presentation] アミロイド病理形成におけるネプリライシンおよびインスリン分解酵素の新知見 (2015)
  • Author(s): 佐藤亘、斉藤貴志、西道隆臣
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-03
• [Presentation] 次世代型アルツハイマー病モデルマウス脳におけるグルタチオン量減少メカニズムの解析 (2015)
  • Author(s): 橋本翔子、斉藤貴志、西道隆臣
  • Organizer: BMB2015
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-01
• [Presentation] アルツハイマー病研究に資するモデルマウスの開発と応用 (2015)
  • Author(s): 斉藤貴志、西道隆臣
  • Organizer: 日本認知症学会
  • Place of Presentation: リンクステーションホール青森
  • Year and Date: 2015-10-04
• [Presentation] APPノックインマウスにおけるリン酸化タウ病態の解析 (2015)
  • Author(s): 塚越 かおり, 藤岡 亮, 細木 恵美, 高野 二郎, 斉藤 貴志, 高島 明彦, 西道 隆臣
  • Organizer: 日本認知症学会
  • Place of Presentation: リンクステーションホール青森
  • Year and Date: 2015-10-03
• [Presentation] Research resource of mouse models for Alzheimer's disease (2014)
  • Author(s): 斉藤 貴志、西道隆臣
  • Organizer: 日本生化学会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Generation and application of single APP locus knockin model mice of Alzheimer’s disease (2014)
  • Author(s): Takashi Saito, Yukio Matsuba, Naomi Mihira, Takaomi C. Saido
  • Organizer: Alzheimer Association International Conference 2014
  • Place of Presentation: コペンハーゲン（デンマーク）
  • Year and Date: 2014-07-12 – 2014-07-17
• [Book] Chronic Inflammation-Mechanisms and Regulation (2016)
  • Author(s): Takashi Saito
  • Total Pages: 11
  • Publisher: Springer