Elucidation of a neurodegenerative mechanism induced by a new Alzheimer's disease drug target and its inhibition

• Project/Area Number: 26293075
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Foundation for Biomedical Research and Innovation
• Principal Investigator: Hoshi Minako 公益財団法人先端医療振興財団, その他部局等, 研究員 (30374010)
• Co-Investigator(Kenkyū-buntansha): 廣明 秀一 名古屋大学, その他の研究科, 教授 (10336589) ; 大西 隆之 公益財団法人先端医療振興財団, その他部局等, 研究員 (30418959)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 神経細胞死 / 神経変性疾患 / ナトリウムポンプ / 立体構造 / 新規創薬ターゲット / 脳神経疾患 / シグナル伝達 / 蛋白質 / 構造解析

Outline of Final Research Achievements

Alzheimer's disease is a disorder that causes cognitive decline due to death of mature neurons, but the cause and mechanism of this death of mature neurons had been unknown.
In this work, we showed for the first time that an assembly, a 30-mer of amyloid-β protein, (which we termed amylospheroids) binds to the sodium pump essential for the survival and function of mature neurons and cause death of mature neurons by suppressing the pump function through this binding. In addition, we showed that peptides that bind to amylospheroids inhibit the death of mature neurons by blocking amylospheroids' binding to the sodium pump, and opened up a path to treatment.
We also clarified the tertiary structure of amylospheroids and showed that amylospheroids havd a specific three-dimensional structure.

Research Products

• [Int'l Joint Research] UCLA/University of Illinois at Chicago(米国)
• [Journal Article] Nuclear magnetic resonance evidence for the dimer formation of beta amyloid peptide 1-42 in 1,1,1,3,3,3-hexafluoro-2-propanol (2016)
  • Author(s): Shigemitsu, Y., Iwaya, N., Goda, N., Matsuzaki, M., Tenno, T., Narita, A., Hoshi, M., *Hiroaki, H.
  • Journal Title: Analytical Biochemistry Volume: 498 Pages: 59-67
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] アルツハイマー病神経細胞死の新たなターゲット分子NA+K+-ATPase ポンプのα3サブユニット (2016)
  • Author(s): 星美奈子
  • Journal Title: 医学のあゆみ Volume: 258 Pages: 247-248
• [Journal Article] Nuclear magnetic resonance evidence for the dimer formation of beta amyloid peptide 1-42 in 1,1,1,3,3,3-hexafluoro-2-propanol (2016)
  • Author(s): Shigemitsu, Y., Iwaya, N., Goda, N., Matsuzaki, M., Tenno, T., Narita, A., Hoshi, M.
  • Journal Title: Analytical Biochemistry Volume: **
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Aβ（1-42）fibril structure illuminates self-recognition and replication of amyloid in Alzheimers’s disease (2015)
  • Author(s): Xiao, Y., Ma. B., McElheny, D., Parthasarathy, S., Long, F., Hoshi, M., Nussinov, R., and * Ishii, Y.
  • Journal Title: Nature Str. Mol. Biol. Volume: 22 Pages: 499-497
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloidby Solid-state NMR (2015)
  • Author(s): Parthasarathy, S., Inoue, M., Xiao, Y., Matsumura, Y., Nabeshima, Y., Long, F., Hoshi, M., and *Ishii, Y.
  • Journal Title: J. Amer. Chem. Soc. Volume: 137 Pages: 6480-6483
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Na,K-ATPase 3 is a death target of Alzheimer patient amyloid-assembly (2015)
  • Author(s): Ohnishi, T., et al.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 112
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Yiling Xiao,Buyong Ma,Dan McElheny,Sudhakar Parthasarathy,Fei Long,Minako Hoshi, Ruth Nussinov & *Yoshitaka Ishii (2015)
  • Author(s): Yiling Xiao,Buyong Ma,Dan McElheny,Sudhakar Parthasarathy,Fei Long,Minako Hoshi, Ruth Nussinov and *Yoshitaka Ishii
  • Journal Title: Nature structural＆molecular biology Volume: **
  • Peer Reviewed
• [Journal Article] Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloid β by Solid-state NMR (2015)
  • Author(s): Sudhakar Parthasarathy, Masafumi Inoue, Yiling Xiao,Yoshitaka Matsumura,Yo-ichi Nabeshima, Fei Long, Minako Hoshi, and *Yoshitaka Ishii
  • Journal Title: J. of the American Chemical Society Volume: **
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Na+,K+-ATPaseα3 Is a New Death Target of Alzheimer Amyloid-beta Assembly (2016)
  • Author(s): Hoshi, M.
  • Organizer: Faculty Lecture
  • Place of Presentation: KU LEUVEN, Belgium
  • Year and Date: 2016-11-05
  • Invited
• [Presentation] ATP1A3 as target of beta-amyloid assembly (2016)
  • Author(s): Hoshi, M.
  • Organizer: 5th Symposium on ATP1A3 in Disease
  • Place of Presentation: UCL Institute of Neurology,London, UK
  • Year and Date: 2016-08-24
  • Int'l Joint Research / Invited
• [Presentation] Neurotoxic, high-mass amyloid beta assemblies, amylospheroids, are formed in the Golgi apparatus of neurons that express amyloid precursor proteins with familial Alzheimer mutations (2016)
  • Author(s): Komura,H., Arai,Y., Matsumura,S., Hoshi,M.
  • Organizer: Gordon Research Conference / Neurobiology of Brain Disorders
  • Place of Presentation: PGA Catalunya Business and Convention Centre
  • Year and Date: 2016-08-07
  • Int'l Joint Research
• [Presentation] 球になると毒になる？アルツハイマー病の脳でなぜ神経細胞が死ぬのか？ (2016)
  • Author(s): 星美奈子
  • Organizer: Lecture series no.140 京都大学総合博物館
  • Place of Presentation: 京都
  • Year and Date: 2016-06-11
  • Invited
• [Presentation] 新たなアルツハイマー病の発生機構 (2016)
  • Author(s): 星美奈子
  • Organizer: バイオファイナンスギルド第14期 第14回セミナー
  • Place of Presentation: 東京
  • Year and Date: 2016-06-10
  • Invited
• [Presentation] アルツハイマー病患者脳由来のアミロイドβ凝集体アミロスフェロイドの発見から成熟神経細胞死の分子機構の解明までの道のり (2016)
  • Author(s): 星美奈子
  • Organizer: 新潟大学脳神経研究会
  • Place of Presentation: 新潟
  • Year and Date: 2016-02-01
  • Invited
• [Presentation] アルツハイマー病で起こる神経細胞死の新たな分子メカニズムの発見と革新的治療法の開発 (2016)
  • Author(s): 星美奈子
  • Organizer: 第4回AAA（Academy of Aging and Cardiovascular-Diabetes Research）
  • Place of Presentation: 東京
  • Year and Date: 2016-01-09
  • Invited
• [Presentation] アルツハイマー病患者脳由来のアミロイドβ凝集体アミロスフェロイドの発見から成熟神経細胞の分子機構の解明までの道のり (2015)
  • Author(s): 星美奈子
  • Organizer: 構造細胞生物学持論／細胞生物学持論
  • Place of Presentation: 東京
  • Year and Date: 2015-12-17
  • Invited
• [Presentation] Na+,K+-ATPaseα3 Is a New Death Target of Alzheimer Amyloid-Assembly (2015)
  • Author(s): Hoshi, M.
  • Organizer: Faculty lecture
  • Place of Presentation: KU LEUVEN, Belgium
  • Year and Date: 2015-11-05
  • Int'l Joint Research / Invited
• [Presentation] Na+,K+-ATPaseα3 Is a New Death Target of Alzheimer Amyloid-Assembly, (2015)
  • Author(s): Hoshi, M.
  • Organizer: 4th International European Neurodegenerative Diseases & Optogenetics Europe-2015 Meeting
  • Place of Presentation: University of Cambridge, UK
  • Year and Date: 2015-11-02
  • Int'l Joint Research / Invited
• [Presentation] アルツハイマー病で起こる神経細胞死の新たなターゲット分子の発見 (2015)
  • Author(s): 星美奈子
  • Organizer: 第4回食品薬品生物構造学研究会
  • Place of Presentation: 静岡
  • Year and Date: 2015-10-20
  • Invited
• [Presentation] Calcium-mediated neurotoxicity of high-mass amyloid-beta assembly, amylospheroids (ASPD) to mature hippocampal neurons through activation of voltage-gated calcium channels (2014)
  • Author(s): Ohnishi T, Sasahara T, Komura H, Arai Y, Nishiyama T, Hoshi M
  • Organizer: Society for Neuroscience 2014
  • Place of Presentation: Washington, D.C.
  • Year and Date: 2014-11-15
• [Presentation] ヒトアルツハイマー病（AD）患者由来アミロイドβ凝集体による新たな神経細胞死機構の解明と病態解明に基づくAD新規治療法の研究開発 (2014)
  • Author(s): 星 美奈子
  • Organizer: 第56回日本老年医学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2014-06-12
  • Invited
• [Book] Peptide Self-‐Assembly: Methods and Protocols (2016)
  • Author(s): Yiling Xiao, Dan McElheny, Minako Hoshi, and Yoshitaka Ishii
  • Publisher: Springer
• [Remarks]
  • URL: http://www.alzforum.org/news/research-news/danger-s-bends-new-structure-av42-fibrils-comes-view
• [Remarks]
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2015/150505_3.html