Investigation of the synaptic dissociation mechanism

• Project/Area Number: 18500263
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Kyoto University
• Principal Investigator: KINOSHITA Ayae Kyoto University, Graduate School of Medicine, Assistant Professor (80321610)
• Co-Investigator(Kenkyū-buntansha): UEMURA Kengo Kyoto University, Graduate School of Medicine, Assistant Professor (00378663)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000); Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Alzheimer's disease / presenilin / synapse / phosphorylation / signal transduction / cadherin / catenin / シナプス可塑性 / N-cadherin

Research Abstract

In order to investigate the mechanism of synaptic dissociation which underlies the synaptic plasticity, we focused on the functions of neuronal adhesion molecules, N-cadherin. N-cadherin is an adhesion molecule, which adheres synaptic clefts in the brain. These adhesion molecules are recently reported to cleaved by several secretases, such as gamma-secretase. After the cleavage in the membranous portion, its cytoplasmic fragment is released into the cytoplasm and enters the nucleus, then plays a role as a modulator of the transactivation. This process is called "Regulated intramembrane proteolysis (RIP)". By using the mouse primary neurons we confirmed that N-cadherin was actually cleaved by some stimuli, and the translocation of its cytoplasmic fragment upregulation of beta-catenin which is an essential molecule for neuronal growth and differentiation. We speculated that this process is also important in vivo, so to confirm in vivo relevancy, we started to generate mutant PS1 (gamma-secretase)-knock-in mouse in which N-cadherin is not cleaved by gamma-secretase. We have already got the F1 hetero mouse. We hope this study will reveal a new insight into synaptic dissociation caused by secretase-mediated cleavages. We would like to deepen this result and hope to elucidate the underlying mechanism of synaptic plasticity. Since gamma-secretase is one of the important targets for the treatment of Alzheimer's disease, our research may help us understand the pathological mechanism of Alzheimer's disease.

Research Products

• [Journal Article] γセクレターゼとシナプス機能 (2008)
  • Author(s): 植村健吾、安藤功一、久保田正和、木下彩栄
  • Journal Title: Cognition and Dementia 7 Pages: 46-54
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Gamma-secretase and synaptic function (2008)
  • Author(s): Kengo, Uemura, Koichi, Ando, Masakazu, Kubota, Ayae, Kinoshita
  • Journal Title: Cognition and Dementia 7 Pages: 46-54
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] GSK3beta activity modifies the localization and function of presenilinl. (2007)
  • Author(s): Uemura K., Kuzuya A., Shimozono Y., Aoyagi N., Ando K., Shimohama S., & Kinoshita A.
  • Journal Title: Journal of Biological Chemistry 282 Pages: 15823-32
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Amyloid beta inhibits ectodomain shedding of N-cadherin via down-regulation of cell-surface NMDA receptor. (2007)
  • Author(s): Uemura, K., Kuzuya, A., Aoyagi, N., Ando, K., Shimozono, Y., Ninomiya, H., Shimohama, S., & Kinoshita, A.
  • Journal Title: Neuroscience 145 Pages: 5-10
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] GSK3beta activity modifies the localization and function of presenilin1 (2007)
  • Author(s): Uemura, K., Kuzuya, A., Shimozono, Y., Aoyagi, N., Ando, K., Shimohama, S., Kinoshita, A
  • Journal Title: Journal of Biological Chemistry 282 Pages: 15823-32
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Amyloid beta inhibits ectodomain shedding of N-cadherin via down-regulation of cell-surface NMDA receptor (2007)
  • Author(s): Uemura, K., Kuzuya, A., Aoyagi, N., Ando, K., Shimozono, Y., Ninomiya, H., Shimohama, S., Kinoshita, A
  • Journal Title: Neuroscience 145 Pages: 5-10
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Amyloid beta inhibits ectodomain shedding of N-cadherinvia down-regulation of cell-surface NMDA receptor. (2007)
  • Author(s): Uemura, K., Kuzuya, A., Aoyagi, N., Ando, K., Shimozono, Y., Ninomiya, H., Shimohama, S., & Kinoshita, A.
  • Journal Title: Neuroscience 145 Pages: 5-10
  • Peer Reviewed
• [Journal Article] Amyloid beta inhibits ectodomain shedding of N-cadherin via down-regulation of cell-surface NMDA receptor. (2007)
  • Author(s): Uemura K., Kuzuya, A., Aoyagi, N., Ando, K., Shimozono, Y., Ninomiya, H., Shimohama, S., Kinoshita, A.
  • Journal Title: Neuroscience 145
• [Journal Article] プレセニリン・γセクレターゼによるシナプスタンパク質転写制御機構 (2006)
  • Author(s): 木下彩栄、植村健吾、安藤功一
  • Journal Title: 生化学 78 Pages: 965-972
  • NAID: 10018335119
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activity-dependent regulation of beta-catenin via epsilon-cleavage of N-cadherin. (2006)
  • Author(s): Uemura K, Kihara T, Kuzuya A, Okawa K, Nishimoto T, Bito H, Ninomiya H, Sugimoto H, *Kinoshita A, Shimohama S.
  • Journal Title: Biochem Biophys Res Commun. 345 Pages: 951-958
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Characterization of sequential N-cadherin cleavage by ADAM10 and PSl. (2006)
  • Author(s): Uemura K, Kihara T, Kuzuya A, Okawa K, Nishimoto T, Ninomiya H, Sugimoto H, *Kinoshita A, Shimohama S.
  • Journal Title: Neurosci Lett. 402 Pages: 278-283
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] The regulatory mechanism of synaptic protein translation By PS1/gamma-secretase (2006)
  • Author(s): Ayae, Kinoshita, Kengo, Uemura, Koichi, Ando
  • Journal Title: Seikagaku 78 Pages: 965-972
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Activity-dependent regulation of beta-catenin via epsilon-cleavage of N-cadherin (2006)
  • Author(s): Uemura, K., Kihara, T., Kuzuya, A., Okawa, K., Nishimoto, T., Bito, H., Ninomiya, H., Sugimoto, H., Kinoshita, A., Shimohama, S
  • Journal Title: Biochem Biophys Res Commun 345 Pages: 951-958
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of sequential N-cadherin cleavage by ADAMIO. and PS1 (2006)
  • Author(s): Uemura, K., Kihara, T., Kuzuya, A., Okawa, K., Nishimoto, T., Bito, H., Ninomiya, H., Sugimoto, H., Kinoshita, A., Shimohama, S
  • Journal Title: Neurosci Lett 402 Pages: 278-283
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of N-cadherin cleavage by ADAM10 and Presenilin 1. (2006)
  • Author(s): Uemura, K., Kihara T, Kuzuya, A., Okawa, K., Sugimoto H, Kinoshita, A*, Shimohama S.* (*shared last author)
  • Journal Title: Neuroscience Letters 402 Pages: 278-283
• [Journal Article] Modulation of beta-catenin nuclear signaling via epsilon-cleavage of N-cadherin. (2006)
  • Author(s): Uemura, K., Kihara T., Kuzuya, A., Okawa, K., Bito H, Ninomiya H, Sugimoto H, Kinoshita, A*, Shimohama S.* (*shared last author)
  • Journal Title: Biochem Biophys Res Commun 345 Pages: 951-958
• [Presentation] 高齢者介護における精神的問題 (2008)
  • Author(s): 日吉和子、カール・ベッカー、木下彩栄
  • Organizer: 第78回日本衛生学会
  • Place of Presentation: 熊本
  • Year and Date: 2008-03-31
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 細胞の接着状態によるgammaセクレターゼの構造と切断機能の調節 (2007)
  • Author(s): 木下彩栄
  • Organizer: 第30回日本分子生物学会年会
  • Place of Presentation: 東京
  • Year and Date: 2007-12-14
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Gamma-secretase function and structure affected by cell-cell adhesion (2007)
  • Author(s): Ayae, Kinosnita
  • Organizer: 30th Japan Molecular Biology
  • Place of Presentation: Tokyo
  • Year and Date: 2007-12-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 介護における殺人の傾向 (2007)
  • Author(s): 日吉和子、カール・ベッカー、木下彩栄
  • Organizer: 第11回日本健康福祉政策学会
  • Place of Presentation: 岡山
  • Year and Date: 2007-12-08
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] N-cadherin enhances extracellular secretion of Abeta and modulates Abeta42/40 ratio. (2007)
  • Author(s): 植村健吾、青柳信寿、安藤功一、高橋良輔、下濱俊、木下彩栄
  • Organizer: 第26回日本認知症学会
  • Place of Presentation: 大阪
  • Year and Date: 2007-10-07
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Tne N-cadherin enhances extracelluar secretion of Abeta and modulates Ab40/42 ratio (2007)
  • Author(s): Uemura, K., Aoyagi, N., Ando, K., Takahashi, R., Shimohama, S., Kinoshita, A
  • Organizer: 26th Japan Society for Dementia
  • Place of Presentation: Osaka
  • Year and Date: 2007-10-07
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] カドヘリン切断に対するアミロイドβ蛋白の影響 (2007)
  • Author(s): 植村健吾、青柳信寿、安藤功一、高橋良輔、下濱俊、木下彩栄
  • Organizer: 第48回日本神経学会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The effect of amyloid beta protein on cadherin cleavage (2007)
  • Author(s): Uemura, K., Aoyagi, N., Ando, K., Takahashi, R., Shimohama, S., Kinoshita, A
  • Organizer: 48th Japan Society of Neurologica
  • Place of Presentation: Nagoya
  • Year and Date: 2007-05-16
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] プレセニリンの基質切断機構 (2007)
  • Author(s): 木下彩栄
  • Organizer: 第127年会日本薬学会 シンポジウム
  • Place of Presentation: 富山
  • Year and Date: 2007-03-30
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Presenilin-mediated substrate cleavage (2007)
  • Author(s): Ayae, Kinoshita
  • Organizer: 127th Japan Pharmaceutical Society
  • Place of Presentation: Toyama
  • Year and Date: 2007-03-30
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 神経変性疾患のサイエンス (2007)
  • Author(s): 木下彩栄 他(高橋良輔 編)
  • Total Pages: 247
  • Publisher: 南山堂
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 神経変性疾患のサイエンス (2007)
  • Author(s): 木下彩栄, 他 (高橋良輔 編)
  • Total Pages: 247
  • Publisher: 南山堂