Implication of ER stress in amyloid production and its application for therapeutic approach

• Project/Area Number: 17591210
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: KUDO Takashi Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (10273632)
• Co-Investigator(Kenkyū-buntansha): TAKEDA Masatoshi Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00179649) ; TANAKA Toshihisa Osaka University, Graduate School of Medicine, Lecture, 医学系研究科, 講師 (10294068) ; OKOCHI Masayasu Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (90335357) ; TAGAMI Shinji Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (40362735) ; 紙野 晃人 大阪大学, 医学系研究科, 助手 (40307955)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: Alzheimer disease / endoplasmic reticulum stress / amyloid apoptosis / APP / chaperone / cerebral ischemia / apoptosis

Research Abstract

Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases. In a screen for compounds that induce the ER-mediated chaperone BiP/GRP 78 (BiP), we identified BiP inducer X (BIX). BIX induced BiP only, in a dose-dependent manner, without induction of other molecules involved in the ER stress response. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction the number of apoptotic cells.
According to our report, BiP binds amyloid precursor protein (APP) to alter the localization of APP to early compartments of the secretory pathway and reduce A β production. In this study, we showed that BIX reduced A β production by its BiP induction property. Taken together, BIX may be a potential therapeutic agent for Alzheimer disease.

Research Products

• [Journal Article] Altered localization of amyloid precursor protein under endoplasmic reticulum stress (2006)
  • Author(s): Kudo T, et al.
  • Journal Title: Biochem Biophys Res Commun 344 Pages: 525-530
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Formation of Tau Inclusions in Knock-in Mice with Familial Alzheimer Disease (FAD) Mutation of Presenilin 1 (PS1) (2006)
  • Author(s): Kentaro Tanemura, Du-Hua Chui, Tetsuya Fukuda, Miyuki Murayama, Jung-Mi Park, Takumi Akagi, Yoshitaka Tatebayashi, Tomohiro Miyasaka, Tetsuya Kimura, Tsutomu Hashikawa, Yuka Nakano, Takashi Kudo, et al.
  • Journal Title: J. Biol. Chem. 281 Pages: 5037-5041
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Presenilin-Dependent Y-Secretase on Plasma Membrane and Endosomes Is Functionally Distinct (2006)
  • Author(s): Akio Fukumori, Masayasu Okochi, Shinji Tagami, Jinwei Jiang, Naohiro Itoh, Taisuke Nakayama, Kanta Yanagida, Yoshiko Ishizuka-Katsura, Takashi Morihara, Kojin Kamino, Toshihisa Tanaka, Takashi Kudo, et al.
  • Journal Title: Biochemistry 45 Pages: 4907-4914
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Possible Role of Scavenger Receptor SRCL in the Clearance of Amyloid-B in Alzheimer's Disease (2006)
  • Author(s): Kenji Nakamura, Wakana Ohya, Hiroshi Funakoshi, Gaku Sakaguchi, Akira Kato, Masatoshi Takeda, Takashi Kudo, et al.
  • Journal Title: J Neurosci Res 84 Pages: 874-890
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A β induces endoplasmic reticulum stress causing possible proteasome impairment via the endoplasmic reticulum-associated degradation pathway (2006)
  • Author(s): Daisuke Kanayama, Takashi Kudo, Ryo Kimura, Nobuhiko Tabuchi, Akio Fukumori, Takashi Morihara, Shinji Tagami, Hisashi Tanii, Masayasu Okochi, Kojin Kamino, Toshihisa Tanaka, Kazunori Imaizumi, Takeshi Tabira, Masatoshi Takeda
  • Journal Title: Psychogeiatrics 6(3) Pages: 100-106
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition ofendocytosis activates alternative degradation pathway of β APP in cultured cells (2006)
  • Author(s): Akio Fukumori, Jingwei Jiang, Hisashi Tanii, Takashi Morihara, Kojin Kamino, Toshihisa Tanaka, Takashi Kudo, Naohiro Ito, Shinji Tagami, Masayasu Okochi, Masatoshi Takeda
  • Journal Title: Psychogeiatrics 6(3) Pages: 107-113
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Altered localization of amyloid precursor protein under endoplasmic reticulum stress. (2006)
  • Author(s): Kudo T, Okumura M, Imaizumi K, Araki W, Morihara T, Tanimukai H, Kamagata E, Tabuchi N, Kimura R, Kanayama D, Fukumori A, Tagami S Okochi M, Kubo M, Tanii H, Tohyama M, Tabira T, Takeda M
  • Journal Title: Biochem Biophys Res Commun. 344 Pages: 525-530
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Formation of Tau Inclusions in Knock-in Mice with Familial Alzheimer Disease (FAD) Mutation of Presenilin 1 (PS1) (2006)
  • Author(s): Kentaro Tanemura, Du-Hua Chui, Tetsuya Fukuda, Miyuki Murayama, Jung-Mi Park, Takumi Akagi, Yoshitaka Tatebayashi, Tomohiro Miyasaka, Tetsuya Kimura, Tsutomu Hashikawa, Yuka Nakano, Takashi Kudo, Masatoshi Takeda, Akihiko Takashima
  • Journal Title: J.Biol.Chem. 281(8) Pages: 5037-5041
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Presenilin-Dependent γ-Secretase on Plasma Membrane and Endosomes Is Functionally Distinct (2006)
  • Author(s): Akio Fukumori, Masayasu Okochi, Shinji Tagami, Jinwei Jiang, Naohiro Itoh, Taisuke Nakayama, Kanta Yanagida, Yoshiko Ishizuka-Katsura, Takashi Morihara, Kojin Kamino, Toshihisa Tanaka, Takashi Kudo, Hisashi Tanii, Akiko Ikuta, Chistian Haass, Masatoshi Takeda
  • Journal Title: Biochemistry 45 Pages: 4907-4914
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Possible Role of Scavenger Receptor SRCL in the Clearance of Amyloid-β in Alzheimer's Disease. (2006)
  • Author(s): Kenji Nakamura, Wakana Ohya, Hiroshi Funakoshi, Gaku Sakaguchi, Akira Kato, Masatoshi Takeda, Takashi Kudo, Toshikazu Nakamura
  • Journal Title: J Neurosci Res 84 Pages: 874-890
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aβ induces endoplasmic reticulum stress causing possible proteasome impairment via the endoplasmic reticulum-associated degradation pathway (2006)
  • Author(s): Daisuke Kanayama, Takashi Kudo, Ryo Kimura, Nobuhiko Tabuchi, Akio Fukumori, Takashi Morihara, Shinji Tagami, Hisashi Tanii, Masayasu Okochi, Kojin Kamino, Toshihisa Tanaka, Kazunori Imaizumi, Takeshi Tabira, Masatoshi Takeda
  • Journal Title: Psychogeiatrics 6(3) Pages: 100-106
  • NAID: 10019375777
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 小胞体ストレスのシャペロン誘導特集アルツハイマー病診断・治療の新しい展開 (2006)
  • Author(s): 工藤 喬, 今泉和則, 原英彰, 武田雅俊
  • Journal Title: Pharma Medica 5 Pages: 59-62
• [Journal Article] 小胞体ストレス (2006)
  • Author(s): 工藤 喬, 武田雅俊
  • Journal Title: 臨床精神医学 35 Pages: 1026-1027
• [Journal Article] Formation of Tau Inclusions in Knock-in Mice with Familial Alzheimer Disease(FAD) Mutation of Presenilin 1(PS1) (2006)
  • Author(s): Kentaro Tanemura, Du-Hua Chui, Tetsuya Fukuda, Miyuki Murayama, Jung-Mi Park, Takumi Akagi, Yoshitaka Tatebayashi, Tomohiro Miyasaka, Tetsuya Kimura, Tsutomu Hashikawa, Yuka Nakano, Takashi Kudo. et al.
  • Journal Title: J. Biol. Chem. 281 Pages: 5037-5041
• [Journal Article] Possible Role of Scavenger Receptor SRCL in the Clearance of Amyloid-β in Alzheimer's Disease (2006)
  • Author(s): Kenji Nakamura, Wakana Ohya, Hiroshi Funakoshi, Gaku Sakaguchi, Akira Kato, Masatoshi Takeda, Takashi Kudo, et al.
  • Journal Title: J Neurosci Res 84 Pages: 874-890
• [Journal Article] Double-strand RNA dependent protein kinase (PKR) is involved in the extrastriatal degeneration in Parkinson's disease and Huntington's disease (2005)
  • Author(s): Yoshio Bando, Reiko Onuki, Taiichi Katayama, Takayuki Manabe, Takashi Kim, et al.
  • Journal Title: Neurochem Int 46 Pages: 11-18
• [Journal Article] Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2 (2005)
  • Author(s): Hua-Qin Wang, Yoshifumi Nakaya, Zhenyu Du, Takuya Yamane, Michiko Shirane, Takashi Kudo, et al.
  • Journal Title: Human Molecular Genetics 14 Pages: 1889-1902
  • NAID: 120005713692
• [Journal Article] BPSDの総論 (2005)
  • Author(s): 工藤 喬, 武田雅俊
  • Journal Title: 老年精神医学雑誌 16 Pages: 9-15
• [Journal Article] 精神医学用語解説287.分子シャペロン (2005)
  • Author(s): 工藤 喬, 武田雅俊
  • Journal Title: 臨床精神医学 33 Pages: 1516-1518
  • NAID: 40006502073
• [Journal Article] 臨床治験の現状と課題 認知症に対する薬物 (2005)
  • Author(s): 工藤 喬, 武田雅俊
  • Journal Title: 臨床精神薬理 9 Pages: 29-34
• [Book] 老年期認知症ナビゲーター (2006)
  • Author(s): 工藤 喬, 武田雅俊
  • Total Pages: 319
  • Publisher: メディカルレビュー社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Recent Progress in Alzheimer's and Parkinson's Disease (2005)
  • Author(s): T.Kudo, T.Katayama, K.Imaizumi, D.Kanayama, J.Hitomi, M.Okochi, M.Tohyama, M.Takeda
  • Total Pages: 383
  • Publisher: Alzheimer pathology and endoplasmic reticulum stress
• [Patent(Industrial Property Rights)] 分子シャペロン発現誘導剤 (2006)
  • Inventor(s): 工藤 喬他
  • Industrial Property Rights Holder: 工藤 喬
  • Industrial Property Number: 2006-124457
  • Filing Date: 2006-04-27
  • Description: 「研究成果報告書概要(和文)」より