Characterization of gamma-secretase activity in the brain and its significance in the development of Alzheimer's disease

• Project/Area Number: 24500433
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Hokkaido University
• Principal Investigator: MORISHIMA Maho 北海道大学, 薬学研究科(研究院), 客員准教授 (50204722)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: アミロイドβタンパク質 / アルツハイマー病 / γセクレターゼ / 脳

Outline of Final Research Achievements

To learn whether altered brain γ-secretase activity contributes to the deposition of amyloid β-protein (Aβ) in the sporadic Alzheimer’s disease patients, γ-secretase activity in the brain was assessed using in vitro reconstituted Aβ generation system in the presence of CHAPSO. γ-Secretase activity in the brain was regulated in the developmental stage-dependent manner．The regional distribution and age-dependent alteration of the γ-secretase activity were little correlated with various indexes of Aβ deposition as well as risk factors for AD. Thus, the quantitative alteration of γ-secretase activity during aging may not be involved in the pathological Aβ deposition in the brain. Further analysis regarding the modulation of γ-secretase activity (variability of cleavage sites) in the brain is ongoing.

Research Products

• [Journal Article] Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase. (2014)
  • Author(s): Morishima-Kawashima M
  • Journal Title: Frontiers in Physiology Volume: 8 Pages: 463-463
  • DOI: 10.3389/fphys.2014.00463
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased levels of plasma p3-Alcα35, a major fragment of Alcadeinα by γ-secretase cleavage, in Alzheimer's disease (2014)
  • Author(s): Omori C, Kaneko M, Nakajima E, Akatsu H, Waragai M, Maeda M, Moroshima-Kawashima M, Saito Y, Nakaya T, Taru H, Yamamoto T, Asada T, Hata S, Suzuki T. for J-ADNI
  • Journal Title: J. Alzheimers Dis Volume: 39 Issue: 4 Pages: 861-870
  • DOI: 10.3233/jad-131610
  • Peer Reviewed
• [Journal Article] γ-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of β-carboxyl-terminal fragment. (2014)
  • Author(s): Matsumura N, Takami M, Okochi M, Wada-Kakuda S, Fujiwara H, Tagami S, Funamoto S, Ihara Y, Morishima-Kawashima M.
  • Journal Title: J Biol Chem. Volume: 289 Issue: 8 Pages: 51095121-51095121
  • DOI: 10.1074/jbc.m113.510131
  • Peer Reviewed
• [Presentation] ラフトのγセクレターゼによるAPP膜内段階的切断機構． (2012)
  • Author(s): 松村展敬，高見真子，田上真次，大河内正康，井原康夫，森島真帆.
  • Organizer: 第31回日本認知症学会
  • Place of Presentation: つくば国際会議場 (茨城県)
• [Presentation] X11Lの構造変換によるAPPの輸送・代謝制御機構．
  • Author(s): 本館利佳，齋藤優実，森島真帆，齋藤有紀，鈴木利治.
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡県)
• [Presentation] Alcadein代謝産物による機能発現.
  • Author(s): 江波綾佳，朴懿，森島真帆，羽田沙緒里，鈴木利治.
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡県)
• [Presentation] てんかん発作、アルツハイマー病発症におけるX11/X11Lの関与.
  • Author(s): 木村尚紀，齋藤有紀，井上剛，森島真帆，鈴木利治.
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡県)
• [Presentation] Alcadeinのリン酸化.
  • Author(s): 蘇武佑里子，古郡慶子，森島真帆，羽田沙緒里，鈴木利治.
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡県)
• [Presentation] Alcadeinによるkinesin-1活性と膜小胞輸送制御機構.
  • Author(s): 白木柚葉，河野高徳，千葉杏子，森島真帆，山本融，鈴木利治.
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡県)
• [Book] The Biology of Alzheimer Disease (The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease) (2012)
  • Author(s): Ihara Y, Morishima-Kawashima M, Nixon R.
  • Total Pages: 511
  • Publisher: Cold Spring Harbor Laboratory Press