Search for neuronal cell death-inhibiting drugs for Alzheimer's disease-relevant signal transduction

• Project/Area Number: 22590247
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tokyo Medical University
• Principal Investigator: HASHIMOTO Yuuichi 東京医科大学, 医学部, 講師 (00317330)
• Co-Investigator(Renkei-kenkyūsha): MATSUOKA Masaaki 東京医科大学, 医学部, 教授 (70222297)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アルツハイマー病 / 神経細胞死 / アミロイド前駆体蛋白質 / プレセニリン / ヒューマニン / アミロイド前駆体タンパク質 / 神経変性疾患 / サイトカイン / 細胞内シグナル伝達 / 受容体 / 治療薬 / 細胞内シグナル伝

Research Abstract

In this research program, we have examined the neuronal cell death mechanism underlysing Alzhemer’s disease (AD), and identified an antagonist of Humanin (HN) which inhibited AD-relevant neuronal cell death and an endogenous agonist of HN receoptor complex composed of WSX-1, ciliary neurotrophic factor receptor/gp130. The results were: (1) MOCA is the key molecule that unifies APP-mediated death signal to PS-mediated death signal, (2) V-set transmembrane domain containing 2 like inhibited HN’s activity via direct binding, and (3) A series of experiments also showed that calmodulin-like skin protein (CLSP), highly expressed in skin tissues, is transported across blood-brain barrier to the central nervous system. CLSP inhibited familial AD-linked V642I-APP-induced neuronal cell death via its binding to HN receptor following activation of JAK2/STAT3 axisThese results suggest that CLSP play a main role in inhibiting AD-related neuronal death and dysfunction in vivo as a physiological defense factor.

Research Products

• [Journal Article] Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer's disease models via the heterotrimeric Humanin receptor (2013)
  • Author(s): Hashimoto Y, Nawa M, Kurita M, Tokizawa M,Iwamatsu A, Matsuoka M
  • Journal Title: Cell Death Dis Volume: 4 Issue: 3 Pages: 555-555
  • DOI: 10.1038/cddis.2013.80
  • Peer Reviewed
• [Journal Article] MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer 's disease-related mutants of amyloid beta precursor protein and presenilin (2012)
  • Author(s): Tachi N, Hashimoto Y, Matsuoka M
  • Journal Title: Biochem. J Volume: 442 Issue: 2 Pages: 413-422
  • DOI: 10.1042/bj20100993
  • Peer Reviewed
• [Journal Article] Caricasole AVSTM2L is a novel secreted antagonist of the neuroprotective peptide Humanin (2011)
  • Author(s): Rossini L, Hashimoto Y, Suzuki H, Kurita M, Gianfriddo M, Scali C, Roncarati R, Franceschini D, Pollio G, Trabalzini L, Terstappen GC, Matsuoka M
  • Journal Title: FASEB J. Volume: 25 Issue: 6 Pages: 1983-2000
  • DOI: 10.1096/fj.10-163535
  • Peer Reviewed
• [Journal Article] VSTM2L is a novel secreted antagonist of the neuroprotective peptide Humanin (2011)
  • Author(s): Rossini, L, Hashimoto, Y., et al
  • Journal Title: FASEB Journal Volume: 25(In press)
  • Peer Reviewed
• [Journal Article] TAG-1 in an inhibitor of TGFβ2-induced neuronal cell death via amyloid β precursor protein (2010)
  • Author(s): Tachi, N., Hashimoto, Y., et al
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 394 Pages: 119-125
  • Peer Reviewed
• [Journal Article] Humanin and the receptors for Humanin (2010)
  • Author(s): Matsuoka, M., Hashimoto, Y.
  • Journal Title: Molecular Neurobiology Volume: 41 Pages: 22-28
  • Peer Reviewed
• [Presentation] SH3BP5 is essential for Humanin-mediated protection against Alzheimer's disease-relevant toxicity (2013)
  • Author(s): 竹下裕二、橋本祐一、内野博之、松岡正明
  • Organizer: 日本薬理学会第86回大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2013-03-23
• [Presentation] Involvement of MOCA in Alzheimer ' s disease-relevant neuronal cell death via APP and presenilins (2011)
  • Author(s): Hashimoto Y, Tachi N, Matsuoka M
  • Organizer: Society for Neuroscience 2011 Annual Meeting
  • Place of Presentation: ワシントン D.C
  • Year and Date: 2011-11-12
• [Presentation] Involvement of MOCA in Alzheimer's disease-relevant neuronal cell death via APP and presenilins (2011)
  • Author(s): Yuichi Hashimoto
  • Organizer: Society for Neuroscience 2011 Annual Meeting
  • Place of Presentation: 米国ワシントンD.C.
  • Year and Date: 2011-11-12
• [Presentation] Involvement of MOCA in neuronal cell death triggered by familial Alzheimer's disease-linked mutants of APP and presenilins. (2011)
  • Author(s): 橋本祐一、太知信之、名和幹朗、松岡正明
  • Organizer: 日本薬理学会 第84回大会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-16
• [Presentation] Involvement of MOCA in neuronal cell death triggered by familial Alzheimer's disease-linked mutants of APP and presenilins (2011)
  • Author(s): Hashimoto, Y., et al.
  • Organizer: 第84回日本薬理学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-16
• [Presentation] SH3BP5 is essential for Humanin-mediated protection against Alzheimer’s disease-relevant toxicity
  • Author(s): Yuji Takeshita
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場
• [Remarks]
  • URL: http://www.tokyo-med.ac.jp/pharmacol/top.html
• [Remarks]
  • URL: http://www.tokyo-med.ac.jp/pharmacol/top.html