Molecular mechanism of Arctic mutant type of Alzheimer's disease via CHRNA7

• Project/Area Number: 15K06786
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Waseda University
• Principal Investigator: Sawamura Naoya 早稲田大学, ナノ・ライフ創新研究機構, 上級研究員(研究院教授) (40449351)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 精神・神経疾患の病態と治療

Outline of Final Research Achievements

The study was made based on the hypothesis that Arctic Aβ inhibits the neuroprotective function and the molecular mechanism of memory, which is the function of CHRNA7. CHRNA7-overexpressing neuronal cells were used to examine the effects of Arctic Aβ on CHRNA7. As a result, suppression of cell death was observed when nicotine was added to the cells, but addition of Arctic Aβ inhibited the neuroprotective effect. Furthermore, we revealed that ERK1/2 activation is involved in the neuroprotection of CHRNA7 as its downstream signal.

Academic Significance and Societal Importance of the Research Achievements

本研究では、Arctic Aβが選択的にCHRNA7 に結合し、ニューロンにおけるCHRNA7 の機能である神経細胞死抑制効果を阻害しているという研究成果を得ることができた。Arcitc Aβ のCHRNA7 への結合部位が創薬のターゲットである可能性があり、今後はこの結合の阻害物質の同定が必要となる。このように基礎研究によるアルツハイマー病の原因解明ならびに創薬ターゲットを示唆した研究成果となった。

Research Products

• [Journal Article] Cholinergic receptor, nicotinic, alpha 7 as a target molecule of Arctic mutant amyloid β (2018)
  • Author(s): Sawamura Naoya、Ju Ye、Asahi Toru
  • Journal Title: Neural Regeneration Research Volume: 13 Issue: 8 Pages: 1360-1360
  • DOI: 10.4103/1673-5374.235238
  • Peer Reviewed / Open Access
• [Journal Article] Arctic Aβ40 blocks the nicotine-induced neuroprotective effect of CHRNA7 by inhibiting the ERK1/2 pathway in human neuroblastoma cells (2017)
  • Author(s): Ju Ye、Asahi Toru、Sawamura Naoya
  • Journal Title: Neurochemistry International Volume: 110 Pages: 49-56
  • DOI: 10.1016/j.neuint.2017.09.005
  • Peer Reviewed
• [Presentation] Arctic AβによるCHRNA7の神経保護作用の抑制とその分子メカニズムの解析 (2016)
  • Author(s): キョウヨウ、朝日透、澤村直哉
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-12-02
• [Presentation] Arctic mutant amyloid β protein inhibits the functions of α7 nicotinic acetylcholine receptors through specific binding (2016)
  • Author(s): Naoya Sawamura
  • Organizer: SFB645-Symposium
  • Place of Presentation: Bad Breisig, Germany
  • Year and Date: 2016-11-09
  • Int'l Joint Research / Invited
• [Presentation] Determination of the key domains of CHRNA7 in the interacting actions of Arctic mutant Aβ (2015)
  • Author(s): Ye Ju, Toru Asahi, Naoya Sawamura
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ
  • Year and Date: 2015-09-11