Mechanism of action of Alzheimer's disease-related peptide p3-Alc on neurons

• Project/Area Number: 18K07384
• 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: National Institute of Advanced Industrial Science and Technology (2020); Hokkaido University (2018-2019)
• Principal Investigator: Hata Saori 国立研究開発法人産業技術総合研究所, 生命工学領域, 主任研究員 (40581012)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アルツハイマー病

Outline of Final Research Achievements

The rapid increase in the number of patients with Alzheimer's disease (AD), the most common form of dementia, has become a social problem, but no effective treatment has yet been established. In this study, we established a quantitative measurement system for the AD-related peptide p3-Alcβ and conducted quantitative analysis in AD patients. The analysis revealed that p3-Alcβ was decreased with the onset of AD.　Analysis of the physiological function of p3-Alcβ in the brain revealed that p3-Alcβ has a protective effect against AD-causing factor Aβ-induced neurotoxicity, suggesting that p3-Alcβ may be useful as a novel therapeutic target for AD.

Academic Significance and Societal Importance of the Research Achievements

高齢化社会の加速に伴い、特に患者数が多いADへの対策が喫緊の課題となっている。これまでに多数開発されてきたAβをターゲットとしたAD治療薬候補としてとは異なメカニズムによって、本研究で着目した脳内内在性ペプチドであるp3-Alcβは抗AD作用を有することが明らかになった。ADは認知症を発症する20年以上前から脳内において病態変化が起こることから早期診断法の確立も重要なポイントなるが、p3-AlcβはAD発症に伴い減少するため、治療開始をモニターするマーカーとしての有用性も示唆され、AD対処法に診断・治療の両方から貢献しうる。

Research Products

• [Journal Article] Extracellular release of ILEI/FAM3C and amyloid-β is associated with the activation of distinct synapse subpopulations. (2021)
  • Author(s): Nakano M, Mitsuishi Y, Liu L, Watanabe N, Hibino E, Hata S, Saito T, Saido C T, Murayama S, Kasuga K, Ikeuchi K, Suzuki T, Nishimura M
  • Journal Title: Journal of Alzheimer’s disease Volume: 80 Issue: 1 Pages: 159-174
  • DOI: 10.3233/jad-201174
  • NAID: 120007019774
  • Peer Reviewed / Open Access
• [Journal Article] γ-Secretase activity is associated with Braak Senile Plaque stages (2020)
  • Author(s): Kakuda Nobuto、Yamaguchi Haruyasu、Akazawa Kohei、Hata Saori、Suzuki Toshiharu、Hatsuta Hiroyuki、Murayama Shigeo、Funamoto Satoru、Ihara Yasuo
  • Journal Title: The American Journal of Pathology Volume: － Issue: 6 Pages: 1323-1331
  • DOI: 10.1016/j.ajpath.2020.02.009
  • Peer Reviewed / Open Access
• [Journal Article] Amyloidogenic processing of amyloid β protein precursor (APP) is enhanced in the brains of alcadein α-deficient mice (2020)
  • Author(s): Gotoh N、Saito Yi、Hata S、Saito H、Ojima D、Murayama Ci、Shigeta M、Abe T、Konno D、Matsuzaki F、Suzuki T、Yamamoto T
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 28 Pages: 9650-9662
  • DOI: 10.1074/jbc.ra119.012386
  • NAID: 120007116485
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced amyloid-β generation by γ-secretase complex in detergent-resistant membrane microdomains with reduced cholesterol levels (2020)
  • Author(s): Hata S, Hu A, Piao Y, Nakaya T, Taru H, Morishima-Kawashima M, Murayama S, Nishimura M, Suzuki T.
  • Journal Title: Human Molecular Genetics Volume: 29 Issue: 3 Pages: 382-393
  • DOI: 10.1093/hmg/ddz297
  • Peer Reviewed / Open Access
• [Journal Article] Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease (2019)
  • Author(s): Hata S、Omori C、Kimura A、Saito H、Kimura N、Gupta V、Pedrini S、Hone E、Chatterjee P、Taddei K、Kasuga K、Ikeuchi T、Waragai M、Nishimura M、Hu A、Nakaya T、Meijer L、Maeda M、Yamamoto T、Masters CL、Rowe CC、Ames D、Yamamoto K、Martins RN、Gandy S、Suzuki T
  • Journal Title: Alzheimer's & Dementia: Translational Research & Clinical Interventions Volume: 5 Issue: 1 Pages: 740-750
  • DOI: 10.1016/j.trci.2019.09.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides (2018)
  • Author(s): Cam M, Durieu E, Bodin M, Manousopoulou A, Koslowski S, Vasylieva N, Barnych B, Hammock BD, Bohl B, Koch P, Omori C, Yamamoto K, Hata S, Suzuki T, Karg F, Gizzi P, Haber VE, Bencetic Mihaljevic V, Tavcar B, Portelius E, Pannee J, Blennow K, Zetterberg H, Garbis SD, Auvray P, Gerber H, Fraering J, Fraering PC, Meijer L.
  • Journal Title: Journal of Alzheimer's Disease Volume: 62 Issue: 4 Pages: 1663-1681
  • DOI: 10.3233/jad-170875
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The cytoplasmic region of the amyloid β‐protein precursor (APP) is necessary and sufficient for the enhanced fast velocity of APP transport by kinesin‐1 (2018)
  • Author(s): Maoko Tsukamoto Kyoko Chiba Yuriko Sobu Yuzuha Shiraki Yuka Okumura Saori Hata Akira Kitamura Tadashi Nakaya Seiichi Uchida Masataka Kinjo Hidenori Taru Toshiharu Suzuki
  • Journal Title: FEBS Letters Volume: 592 Issue: 16 Pages: 2716-2724
  • DOI: 10.1002/1873-3468.13204
  • Peer Reviewed / Open Access
• [Journal Article] X11 and X11-like proteins regulate the level of extrasynaptic glutamate receptors (2018)
  • Author(s): Motodate Rika、Saito Haruka、Sobu Yuriko、Hata Saori、Saito Yuhki、Nakaya Tadashi、Suzuki Toshiharu
  • Journal Title: Journal of Neurochemistry Volume: 148 Issue: 4 Pages: 480-498
  • DOI: 10.1111/jnc.14623
  • Peer Reviewed / Open Access
• [Presentation] アルツハイマー病新規治療法開発を目指した脳内在性ペプチドの解析 (2020)
  • Author(s): 羽田沙緒里、齋藤遥、木下祥一、鈴木利治
  • Organizer: 第９３回日本生化学会大会
• [Presentation] アルツハイマー脳におけるラフトの脂質変化とγセクレターゼの局在・機能変化 (2020)
  • Author(s): 羽田沙緒里、胡安琪、村山繁雄、森島真帆、西村正樹、鈴木利治
  • Organizer: 第39回日本認知症学会学術集会
• [Presentation] Altered levels of p3-Alcβ peptides in the CSF of aged monkeys and Alzheimer’s disease patients. (2019)
  • Author(s): Saori Hata, Ayano Kimura, Haruka Saito, Masaaki Waragai, Takeshi Ikeuchi, Ralph Martins, Nobuyuki Kimura, Masaki Nishimura, Toshiharu Suzuki
  • Organizer: Alzheimer's Association International Conference 2019
  • Int'l Joint Research
• [Presentation] Enhanced β- and β’-cleavages of APP in Alcadeina knockout mouse brain. (2019)
  • Author(s): Toshiharu Suzuki, Naoya Goto, Haruka Saito, Saori Hata, Tohru Yamamoto
  • Organizer: Alzheimer's Association International Conference 2019
  • Int'l Joint Research
• [Presentation] Prevention of neurons from toxicity induced by Aβ42 by p3-Alcβ peptides and their pharmacokinetics in ice. (2019)
  • Author(s): Haruka Saito, Saori Hata, Toshiharu Suzuki
  • Organizer: Alzheimer's Association International Conference 2019
  • Int'l Joint Research
• [Presentation] Mirochondria as a therapeutic target of Alzheimer’s disease. (2019)
  • Author(s): Toshiharu Suzuki, Saori Hata
  • Organizer: The 7th International ALA and Prophyrin Symposium (IAPS7)
  • Int'l Joint Research / Invited
• [Presentation] 新規AD治療薬候補p3-Alcβの作用メカニズム解明 (2019)
  • Author(s): 羽田沙緒里、齋藤遥、木村彩乃、鈴木利治
  • Organizer: 第38回日本認知症学会学術集会
• [Presentation] Alcadein代謝ペプチドをシードとしたアルツハイマー病新規治療法の開発 (2018)
  • Author(s): 羽田沙緒里、齋藤遥、木村彩乃、鈴木利治
  • Organizer: 第91回日本生化学会大会
• [Presentation] Aβオリゴマーによる神経毒性を緩和するp3-Alcβペプチドのin vitroにおける機能解析 (2018)
  • Author(s): 齋藤 遥, 羽田 沙緒里, 木村 彩乃, 鈴木 利治
  • Organizer: 第91回日本生化学会大会
• [Presentation] γ-セクレターゼ切断産物p3-Alcβペプチドの加齢およびAD発症による産生変化 (2018)
  • Author(s): 羽田沙緒里、木村彩乃、木村展之、池内健、春日健作、藁谷正明、西村正樹、鈴木利治
  • Organizer: 第37回日本認知症学会学術集会
• [Presentation] Aβ毒性から神経を保護するp3-Alcβを用いたアルツハイマー病治療戦略 (2018)
  • Author(s): 鈴木利治、齋藤 遥、木村彩乃、大森智織、羽田沙緒里
  • Organizer: 第37回日本認知症学会学術集会
• [Presentation] Alcadeinβ代謝産物p3-AlcβはAβ及びNMDA誘導性神経毒性を緩和する (2018)
  • Author(s): 齋藤 遥、羽田沙緒里、木村彩乃、大森智織、山本一夫、鈴木利治
  • Organizer: 第37回日本認知症学会学術集会
• [Remarks] 北海道大学大学院薬学研究院 神経科学研空室ホームページ
  • URL: https://www.pharm.hokudai.ac.jp/shinkei/index.html
• [Remarks] 北海道大学 大学院薬学研究院 神経科学研究室
  • URL: https://www.pharm.hokudai.ac.jp/shinkei/index.html
• [Patent(Industrial Property Rights)] パーキンソン病の診断指標 (2019)
  • Inventor(s): 伴（羽田）沙緒里、山本融、正木勉、出口一志、鎌田正紀、ほか7名
  • Industrial Property Rights Holder: 伴（羽田）沙緒里、山本融、正木勉、出口一志、鎌田正紀、ほか7名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] パーキンソン病の診断指標 (2019)
  • Inventor(s): 伴沙緒里、山本融、正木勉、出口一志、鎌田正紀、他7名
  • Industrial Property Rights Holder: 国立大学法人 北海道大学、国立大学法人 香川大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-033661
  • Filing Date: 2019