Role of renin-angiotensin system in regulation of brain amyloid deposition

• Project/Area Number: 19K07846
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Nagoya City University
• Principal Investigator: Zou Kun 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (40450837)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Discontinued (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アルツハイマー病 / アミロイドβタンパク / アンギオテンシン変換酵素 / レニン・アンギオテンシン系 / アンギオテンシン受容体 / Aβ変換活性 / アンギオテンシンII受容体 / 温度変化 / γセクレターゼ / ApoE分泌 / プレセニリン / 知能指数 / ACE阻害薬 / アミロイド / アミロイド蓄積

Outline of Research at the Start

アルツハイマー病(AD)では、アミロイドβ蛋白(Aβ)蓄積機構の解明が重要な課題となっている。中年期の高血圧症はADの危険因子とされているが、血圧調節に重要な役割を担っているレニン・アンギオテンシン系(RA系)とAD分子病態とのin vivoでの関連は不明である。本研究では、RA系の鍵分子とAD分子病態との関連をADモデルマウスを使用して解明し、治療標的分子を明らかにする。

Outline of Final Research Achievements

Midlife hypertension is a risk factor for the onset of Alzheimer's disease (AD).Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In an 8-year longitudinal study, we found that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40-converting activity compared with sera from age-matched healthy individuals. A clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated hAPP/ACE(+/-) mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. Moreover, we clarified that the interaction between angiotensin receptor and β-adrenergic receptor regulates the production of Aβ.

Academic Significance and Societal Importance of the Research Achievements

本研究は、従来高血圧の治療標的であったACEやアンギオテンシン受容体がAD分子病態に関与するという新機能を明らかにした点に独自性と新規性がある。ACE阻害薬やアンギオテンシン受容体拮抗薬が広く降圧剤として使用されていることから、レニン・アンギオテンシン系がADの発症にどう関わっているのか、そのメカニズムを含め分子・細胞・動物レベルで明らかにしておくことは極めて重要である。本研究は、今後の新規アルツハイマー病治療薬の開発においても社会的意義は大きいと思われる。

Research Products

• [Int'l Joint Research] Department of Neuroscience/School of Medicine/Johns Hopkins University(米国)
• [Journal Article] Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis (2022)
  • Author(s): Sadequl Islam, Yang Sun, Yuan Gao, Tomohisa Nakamura, Arshad Ali Noorani, Tong Li, Philip C Wong, Noriyuki Kimura, Etsuro Matsubara, Kensaku Kasuga, Takeshi Ikeuchi, Taisuke Tomita, Kun Zou, Makoto Michikawa
  • Journal Title: J Neurosci Volume: 42 Issue: 8 Pages: 1574-1586
  • DOI: 10.1523/jneurosci.2039-21.2021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Oral dysfunctions and cognitive impairment/dementia (2021)
  • Author(s): Nakamura T, Zou K, Shibuya Y, and Michikawa M
  • Journal Title: J Neurosci Res Volume: 99 Issue: 2 Pages: 518-528
  • DOI: 10.1002/jnr.24745
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cholesterol Regulates Exosome Release in Cultured Astrocytes (2021)
  • Author(s): Mohammad Abdullah, Tomohisa Nakamura, Taslima Ferdous, Yuan Gao, Yuxin Chen, Kun Zou, Makoto Michikawa
  • Journal Title: Front Immunol Volume: 12 Pages: 722581-722581
  • DOI: 10.3389/fimmu.2021.722581
  • Peer Reviewed / Open Access
• [Journal Article] Interaction between Angiotensin Receptor and β-Adrenergic Receptor Regulates the Production of Amyloid β-Protein (2020)
  • Author(s): Kota Kikuchi, Yu Fujita, Xuefeng Shen, Junjun Liu, Tomoki Terakawa, Daiki Nishikata, Sho Niibori, Takayuki Ito, Kazuyuki Ashidate, Takuya Kikuchi, Yu Kikuchi, Tomoji Maeda, Kun Zou, Hiroto Komano
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 4 Pages: 731-735
  • DOI: 10.1248/bpb.b20-00007
  • NAID: 130007825293
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-04-01
  • Peer Reviewed
• [Journal Article] Current Biomarkers for Alzheimer's Disease: From CSF to Blood (2020)
  • Author(s): Kun Zou, Mohammad Abdullah, Makoto Michikawa
  • Journal Title: J Pers Med Volume: 10 Issue: 3 Pages: 85-85
  • DOI: 10.3390/jpm10030085
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High temperature promotes amyloid β-protein production and γ-secretase complex formation via Hsp90 (2020)
  • Author(s): Arshad Ali Noorani, Hitoshi Yamashita, Yuan Gao, Sadequl Islam, Yang Sun, Tomohisa Nakamura, Hiroyuki Enomoto, Kun Zou, Makoto Michikawa
  • Journal Title: J Biol Chem Volume: 295 Issue: 52 Pages: 18010-22
  • DOI: 10.1074/jbc.ra120.013845
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Engulfment of Toxic Amyloid β-protein in Neurons and Astrocytes Mediated by MEGF10 (2020)
  • Author(s): Yu Fujita, Tomoji Maeda, Chiharu Sato, Masaya Sato, Hatsune Hatakeyama, Yume Ota, Nozomi Iwabuchi, Komaki Tatesawa, Ayako Nomura, Kun Zou, Hiroto Komano
  • Journal Title: Neuroscience Volume: 443 Pages: 1-7
  • DOI: 10.1016/j.neuroscience.2020.07.016
  • Peer Reviewed
• [Journal Article] A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice (2019)
  • Author(s): Liu Shuyu、Ando Fujiko、Fujita Yu、Liu Junjun、Maeda Tomoji、Shen Xuefeng、Kikuchi Kota、Matsumoto Aoi、Yokomori Mirai、Tanabe-Fujimura Chiaki、Shimokata Hiroshi、Michikawa Makoto、Komano Hiroto、Zou Kun
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 25 Pages: 9760-9770
  • DOI: 10.1074/jbc.ra118.006420
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Presenilin is essential for ApoE secretion (2021)
  • Author(s): Kun Zou, Sadequl Islam, Yang Sun, Yuan Gao, Tomohisa Nakamura, Arshad Ali Noorani, Tong Li, Philip C Wong, Noriyuki Kimura, Etsuro Matsubara, Kensaku Kasuga, Takeshi Ikeuchi, Taisuke Tomita, Makoto Michikawa
  • Organizer: 第64回日本神経化学会大会
• [Presentation] ApoE分泌におけるプレセニリンの制御作用 (2021)
  • Author(s): Sadequl Islam, Yang Sun, Yuan Gao, Tomohisa Nakamura, Arshad Ali Noorani, Tong Li, Philip C Wong, Noriyuki Kimura, Etsuro Matsubara, Kensaku Kasuga, Takeshi Ikeuchi, Taisuke Tomita, Kun Zou, Makoto Michikawa
  • Organizer: 第40回日本認知症学会学術集会
• [Presentation] Molecular Mechanism of Aβ production regulated by Hsp90 at high temperature (2020)
  • Author(s): 鄒鶤, Noorani Arshad, 山下均, 高原, 孫陽, Islam Sadequl, 中村知寿, 榎本啓之, 道川誠
  • Organizer: 第39回日本認知症学会学術集会
• [Presentation] Role of temperature in production of amyloid beta-protein (2020)
  • Author(s): 鄒鶤, Noorani Arshad, 山下均, 高原, 孫陽, Islam Sadequl, 中村知寿, 榎本啓之, 道川誠
  • Organizer: 第93回日本生化学会
• [Presentation] Heterozygous ACE deletion increases amyloid deposition in mice (2019)
  • Author(s): 鄒鶤
  • Organizer: 第38回日本認知症学会学術集会
• [Presentation] Inhibition of ACE impairs human intelligence and exacerbates Alzheimer's pathology in mice (2019)
  • Author(s): 鄒鶤
  • Organizer: Neuro 2019
• [Presentation] A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice (2019)
  • Author(s): 鄒鶤
  • Organizer: 第92回日本生化学会大会