Identification of a regulatory factor for gamma-secretase activity generating Abeta40/Abeta 42 and its functional analyses

• Project/Area Number: 21500343
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Hokkaido University
• Principal Investigator: MORSHIMA Maho 北海道大学, 大学院・薬学研究院, 特任准教授 (50204722)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アルツハイマー病 / アミロイドβタンパク質 / γセクレターゼ / 脳神経疾患 / アルツハマー病 / APP / プロテアーゼ

Research Abstract

In this study, the lipid rafts were prepared from wild-type mouse embryonic fibroblasts pretreated with a reversible cross-linker and (active) gamma-secretase complexes localized there were isolated by immunoprecipitation and analyzed proteinchemically through LC-MS/MS to identify a regulatory factor for the gamma-secretase activity. Six novel candidates for gamma-secretase components (binding factors) including annexin have been identified. Functional analyses of these candidate molecules involving in Abeta generation are now on-going in cultured cells.

Research Products

• [Journal Article] Dissociation of beta-amyloid from lipoprotein in cerebrospinal fluid from Alzheimer' s disease accelerates beta-amyloid-42 (2011)
  • Author(s): Takamura A, Kawarabayashi T, Yokoseki T, Shibata M, Morishima-Kawashima M, Saito Y, Murayama S, Ihara Y, Abe K, Shoji M, Michikawa M, Matsubara E
  • Journal Title: assembly. Neurosci Res Volume: 89 Issue: 6 Pages: 815-821
  • DOI: 10.1002/jnr.22615
  • Peer Reviewed
• [Journal Article] Gamma-secretase : Successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment (2009)
  • Author(s): Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y
  • Journal Title: J Neurosci Volume: 29 Pages: 13042-13052
  • URL: http://www.jneurosci.org/content/29/41/13042.long
  • Peer Reviewed
• [Journal Article] gamma-Secretase : successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. (2009)
  • Author(s): Takami M, et al.
  • Journal Title: The Journal of Neuroscience 29 Pages: 13042-13052
  • Peer Reviewed
• [Presentation] DRMにおけるγセクレターゼのAPP切断機序 (2012)
  • Author(s): 松村展敬,高見真子,井原康夫,森島真帆
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 北海道大学(札幌市)
  • Year and Date: 2012-03-29
• [Presentation] マウス脳γセクレターゼ活性の解析 (2011)
  • Author(s): 宮本一仁,孫瑜,松村展敬,森島真帆
  • 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: 2011-11-12
• [Presentation] Protein-fragment complementationアッセイ法を用いたタウの凝集体形成過程の解析 (2009)
  • Author(s): 松村展敬,宮坂知宏,千野拓,吉名佐和子,中台枝里子,三谷昌平,井原康夫,森島真帆
  • Organizer: 第28回日本認知症学会
  • Place of Presentation: 東北大学百周年記念会館(仙台市)
  • Year and Date: 2009-11-20
• [Presentation] Protein-fragment complementationアッセイ法を用いたタウの凝集体形成過程の解析 (2009)
  • Author(s): 松村展敬
  • Organizer: 第28回日本認知症学会
  • Place of Presentation: 仙台,東北大学百周年記念会館
  • Year and Date: 2009-11-20
• [Book] The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease. In The Biology of Alzheimer Disease (2012)
  • Author(s): Ihara Y, Morishima-Kawashima M, Nixon R
  • Publisher: Cold Spring Harbor Laboratory Press
• [Book] The Biology of Alzheimer Disease (2012)
  • Author(s): Ihara Y
  • Publisher: Cold Spring Harbor Laboratory Press
• [Book] ユビキチン.認知症学(上)-その解明と治療の最新知見- (2011)
  • Author(s): 森島真帆
  • Total Pages: 620
  • Publisher: 日本臨床