Mutations in the APP in familial Alzheimer's disease increase Abeta oligomer production in cellular models

• Project/Area Number: 25461288
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Yoichi Ohshima 京都府立医科大学, 医学(系)研究科(研究院), 助教 (50516060)
• Co-Investigator(Kenkyū-buntansha): 徳田 隆彦 京都府立医科大学, 医学(系)研究科(研究院), 教授 (80242692) ; 笠井 高士 京都府立医科大学, 医学(系)研究科(研究院), 助教 (70516062)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アルツハイマー病 / Aβオリゴマー / Aβモノマー / アミロイド前駆蛋白 / アミロイドβ蛋白 / ELISA / オリゴマー

Outline of Final Research Achievements

We herein employed the Flp-In T-Rex 293 (T-REx293) cellular system transfected with a single copy of wild-type, Swedish-, Dutch-, or London-type APP, and quantified the levels of Aβ monomers (Aβ1-40 and Aβ1-42) and AβOs using ELISA. The levels of extracellular AβOs were significantly higher in Dutch- and London-type APP-transfected cells than in wild-type APP-transfected cells. Increased levels were also observed in Swedish-type APP-transfected cells. On the other hand, intracellular levels of AβOs were unaltered among wild-type and mutant APP-transfected cells. Intracellular levels of Aβ monomers were undetectable, and no common abnormality was observed in their extracellular levels or ratios (Aβ1-42/Aβ1-40) among the cells examined. We herein demonstrated that increased levels of extracellular AβOs are the common phenotype in cellular models harboring different types of APP mutations. Our results suggest that extracellular AβOs play a key role in the pathogenesis of AD.

Research Products

• [Presentation] 喫煙成分のアミロイドβ蛋白動態への影響 ― 家族性アルツハイマー病細胞モデルを用いた検討 ―. (2015)
  • Author(s): 大島洋一, 岩田和実, 松本みさき, 勝山真人, 衣斐督和, 矢部千尋.
  • Organizer: 第36回日本臨床薬理学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-12-09
• [Presentation] Increased secretion of Abeta-oligomers harboring mutants in cells linked to FAD. (2015)
  • Author(s): 大島洋一， 徳田隆彦， 田口勝敏, 水田依久子, 亀谷富由樹, 田中雅樹, 水野敏樹, 矢部千尋.
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-20
• [Presentation] THE COMMON BIOCHEMICAL PHENOTYPES OF CELLS EXPRESSING APP-MUTANTS LINKED TO FAMILIAL ALZHEIMER'S DISEASE IS INCREASE IN THE SECRETION OF ABETA-OLIGOMERS (2015)
  • Author(s): Y. Ohshima, T. Tokuda, K. Taguchi, I. Mizuta, F. Kametani, M. Tanaka, T. Mizuno, C. Yabe-Nishimura.
  • Organizer: The 12th International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders (ADPD2015)
  • Place of Presentation: フランス
  • Year and Date: 2015-03-18 – 2015-03-22
• [Presentation] 家族性アルツハイマー病に共通するアミロイドβ蛋白動態の検討 (2014)
  • Author(s): 大島洋一, 徳田隆彦, 田口勝敏, 水田依久子, 田中雅樹, 水野敏樹, 矢部千尋.
  • Organizer: 第35回日本臨床薬理学会学術総会.
  • Place of Presentation: 愛媛
  • Year and Date: 2014-12-04 – 2014-12-06
• [Presentation] 多様な細胞モデルでのアミロイドβ蛋白オリゴマーのアルツハイマー病態発現機序の検討
  • Author(s): 大島洋一, 徳田隆彦, 田口勝敏, 水田依久子, 渡邊義久, 水野敏樹, 富山貴美, 亀谷富由樹, 森啓, 田中雅樹, 中川正法, 矢部千尋.
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] 家族性アルツハイマー病に共通するアミロイドβ蛋白の産生量の検討
  • Author(s): 大島洋一, 徳田隆彦, 田口勝敏, 富山貴美, 亀谷富由樹, 田中雅樹, 水野敏樹, 中川正法, 矢部千尋
  • Organizer: 第124回日本薬理学会近畿部会
  • Place of Presentation: 京都