Abeta43-converting enzyme and its role in amyloid deposition

• 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• 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 / アミロイド沈着 / Aβ43変換活性

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] ifferential effects of angiotensin II receptor blockers on Aβ generation. (2014)
  • Author(s): Liu J, Liu S, Tanabe C, Maeda T, Zou K, Komano H
  • Journal Title: Neurosci Lett Volume: 567 Pages: 51-56
  • DOI: 10.1016/j.neulet.2014.03.030
  • Peer Reviewed
• [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 AJ, Zou K, Komano H
  • Journal Title: J Neurosci Res Volume: in press
  • Peer Reviewed
• [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] Aβ43 is the earliest depositing Aβ species 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 Issue: 6 Pages: 2311-2331
  • DOI: 10.1016/j.ajpath.2013.01.053
  • Peer Reviewed
• [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
• [Journal Article] The ubiquitin ligase synoviolin up-regulates amyloid β production by targeting a negative regulator of γ-secretase, Rer1, 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: 287 Issue: 53 Pages: 44203-44211
  • DOI: 10.1074/jbc.m112.365296
  • Peer Reviewed
• [Presentation] Angiotensin type Ia receptor regulates amyloid plaque formation. (2013)
  • Author(s): 鄒鶤，劉俊俊，劉姝余，松本幸乃，村上咲，田邉千晶，前田智司，道川誠，駒野宏人
  • Organizer: 第32回日本認知症学会学術集会
  • Place of Presentation: 松本市
• [Presentation] Angiotensin type Ia receptor deficiency ameliorates amyloid plaque formation. (2013)
  • Author(s): Zou K, Liu J, Liu S, Matsumoto Y, Tanabe C, Maeda T, Michikawa M, Komano H
  • Organizer: 23rd Alzheimer Europe Conference
  • Place of Presentation: Malta
• [Presentation] Angiotensin II type Ia receptor deficiency ameliorates brain amyloid pathology in a transgenic mouse model of Alzheimer’s disease. (2013)
  • Author(s): Liu J, Liu S, Matsumoto Y, Tanabe C, Maeda T, Zou K, Komano H
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜市
• [Presentation] Conversion of Aβ43 to Aβ40 by combination of angiotensin-converting enzyme 2 and angiotensin-converting enzyme. (2013)
  • Author(s): Liu S, Liu J, Miura Y, Tanabe C, Maeda T, Terayama Y, Turner AJ, Zou K, Komano H
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜市
• [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
• [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
• [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
• [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
• [Presentation] Aβ43 is the earliest depositing Aβ species 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: 神戸市
• [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: 神戸市
• [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: 筑波市
• [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: 山形市