Abeta43-converting enzyme and its role in amyloid deposition

2013 Fiscal Year Final Research Report

• Project/Area Number: 24700383
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Iwate Medical University
• Principal Investigator: ZOU KUN 岩手医科大学, 薬学部, 講師 (40450837)
• Co-Investigator(Renkei-kenkyūsha): KOMANO Hiroto 岩手医科大学, 薬学部, 教授 (40170378)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: アルツハイマー病 / アミロイドベータ蛋白 / アンギオテンシン変換酵素

Research Abstract

The longer and neurotoxic species of amyloid beta-protein (Abeta), Abeta42 and Abeta43, contribute to Abeta accumulation in Alzheimer's disease (AD) pathogenesis and are considered to be the primary cause of the disease. In contrast, Abeta40, inhibits amyloid deposition and may have neuroprotective effects. Herein, we provide evidence that Abeta43 deposition appears earlier than Abeta42 and Abeta40 deposition in the brain of mutant amyloid precursor protein transgenic (APPtg) mice, suggesting that Abeta43 is the earliest depositing Abeta species. In addition, we found increased Abeta43 levels and Abeta43/Abeta42 ratio in the serum of AD patients, which may be used as diagnostic blood biomarkers for AD. We further identified the brain Abeta43-to-Abeta42-converting enzyme as ACE2. Notably, the combination of ACE2 and ACE could convert Abeta43 to Abeta40. Thus, maintaining brain ACE2 and ACE activities may be important for preventing brain amyloid neurotoxicity and deposition in AD.

Research Products

• [Journal Article] Differential effects of angiotensin II receptor blockers on Aβgeneration (2014)
  • Author(s): Liu, J., Liu, S., Tanabe, C., Maeda, T., Zou, K., Komano, H.
  • Journal Title: Neurosci Lett Volume: 567 Pages: 51-56
• [Journal Article] Conversion of Aβ43 to Aβ40 by the successive action of angiotensin-converting enzyme 2 and angiotensin-converting enzyme (2014)
  • Author(s): Liu, S., Liu, J., Miura, Y., Tanabe, C., Maeda, T., Terayama, Y., Turner, A.J., Zou, K., Komano, H.
  • Journal Title: J Neurosci Res Volume: (in press)
• [Journal Article] Aβ43 is the earliest depositing Aβspecies in APP transgenic mouse brain and is converted to Aβ41 by two active domains of ACE (2013)
  • Author(s): Zou, K., Liu, J., Watanabe, A., Hiraga, S., Liu, S., Tanabe, C., Maeda, T., Terayama, Y., Takahashi, S., Michikawa, M., Komano, H.
  • Journal Title: Am J Pathol Volume: 182 Pages: 2311-2331
• [Journal Article] The ubiquitin ligase synoviolin up-regulates amyloidβproduction by targeting a negative regulator ofγ-secretase, Rer 1, for degradation (2012)
  • Author(s): Tanabe, C., Maeda, T., Zou, K., Liu, J., Liu, S., Nakajima, T., Komano, H.
  • Journal Title: J. Biol. Chem Volume: 28 Pages: 44203-44211
• [Presentation] Early deposition of Aβ43 in APP transgenic mouse brain (2012)
  • Author(s): 鄒鶤,劉俊俊,渡邉淳,劉姝余,田邉千晶,前田智司,寺山靖夫,高橋智,道川誠,駒野宏人
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: 筑波
  • Year and Date: 20121000
• [Presentation] Analysis of Aβ42-to-Aβ40- converting activity and Aβ43 level in AD patient serum (2012)
  • Author(s): Liu, S., Liu, J., Tanabe, C., Maeda, T., Terayama, Y., Takahashi, S., Zou, K., Komano, H.
  • Organizer: 第11回アジア太平洋神経化学会・第55回日本神経化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 20120900
• [Presentation] Aβ43 is the earliest depositing Aβspecies in APP transgenic mouse brain and is converted to Aβ41 by two active domains of ACE (2012)
  • Author(s): Zou, K., Liu, J., Watanabe, A., Liu, S., Tanabe, C., Maeda, T., Terayama, Y., Takahashi, S., Michikawa, M., Komano, H.
  • Organizer: 第11回アジア太平洋神経化学会・第55回日本神経化学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 20120900
• [Presentation] アルツハイマー病モデルマウスにおけるAβ43の脳内蓄積の解析 (2012)
  • Author(s): 劉姝余,劉俊俊,平賀彩江子,松本幸乃,三浦友希恵,田邉千晶,前田智司,鄒鶤,駒野宏人
  • Organizer: 日本生化学会東北支部第78回例会・シンポジウム
  • Place of Presentation: 山形
  • Year and Date: 20120500