Analysis of sequential endoproteolytic process of beta-APP to establish novel therapeutic interventions

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17390318
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: TAKEDA Masatoshi Osaka University, Graduate School of Medicine, Professor (00179649)
• Co-Investigator(Kenkyū-buntansha): OKOCHI Masayasu Osaka University, Graduate School of Medicine, Assistant (90335357) ; KUDO Takashi Osaka University, Graduate School of Medicine, Associate Professor (10273632) ; TANAKA Toshihisa Osaka University, graduate School of Medicine, Lecturer (10294068) ; TAGAMI Shinji Osaka University, Graduate School of Medicine, Assistant (40362735) ; MORIHARA Takashi Osaka University, Graduate School of Medicine, Assistant (90403196)
• Project Period (FY): 2005 – 2006
• Keywords: Alzheimer disease / Presenilin / gamma-secretase / Notch signaling / Amyloid-beta peptide / beta-amyloid protein precursor / Notch-1 / gamma-cleavage

Research Abstract

We have revealed detailed processes of sequential endoproteolysis of betaAPP and Notch. We have found that novel compound-W is a second generation gamma-secretase inhibitor which inhibits Abeta generation without perturbing Notch signaling. Moreover, we found that Abeta29-40 peptide has an activity to inhibit beta-secretase. Furthermore, we established ELISA system to measure Nbeta level in vivo. In addition, we accidentally found compound-OSX which inhibit beta-cleavage of betaAPP without inhibiting BACE.

Research Products

• [Journal Article] The DYRKIA gene,encoded in chromosome 21 Down syndrome critical region,bridges between beta-amyloid production and tauphosphorylation in Alzheimer disease (2007)
  • Author(s): Kimura R, Kamino K, et. al.
  • Journal Title: Hum Mol Genet. 16(1) Pages: 15-23
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. (2007)
  • Author(s): Kimura R, Kamino K, et. al.
  • Journal Title: Hum Mol Genet. 16(1) Pages: 15-23
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Secretion of the Notch-1 A β-like peptide 」during Notch signaling (2006)
  • Author(s): Okochi M, Fukumori A, Jiang J, Itoh N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M.
  • Journal Title: J Biol Chem. 28(12) Pages: 7890-8
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Presenilin-dependent γ-secretase on plasma membrane and endosomes is functionally distinct (2006)
  • Author(s): Fukumori A, Okochi M, Tagami S, Jiang J, Itoh N, Nakayama T, Yanagida K, Ishizuka-Katsura Y, Morihara T, Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A, Haass C, Takeda M.
  • Journal Title: BIOCHEMISTRY 45(15) Pages: 4907-14
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Development of new screening system for Alzheilzer disease,in vitro A・sink ,assay,toidentify the dissociation of soluble A・from fibrils (2006)
  • Author(s): Sato N, Okochi M, Taniyama Y, Kurinami H, Shimamura LM, Takeuchi D, Hamada H, Fukumori A, Kiyosue K, Taguchi T, Tanaka T, Miyasaka M, Takeda M, Ogihara T, Morishita R
  • Journal Title: Neurobiology of Disease 22(3) Pages: 487-95
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase (2006)
  • Author(s): Yamasaki A, Eimer S, Okochi M, Smialowska A, Kaether C, Baumeister R, Haass C, Steiner H
  • Journal Title: J Neuroscience 5(26) Pages: 3821-3828
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 非ろテロイド性消炎薬(NSAIDs)のA」42産生阻害作用とその応用 (2006)
  • Author(s): 大河内 正康, 田上 真次, 武田 雅俊
  • Journal Title: CURRENT THERAPY Vol 24, No.3 Pages: 33-37
  • 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-beta in Alzheimer's disease (2006)
  • Author(s): Nakamura K, Ohya W, Funakoshi H, Sakaguchi G, Kato A, Takeda M, Kudo T, Nakamura T.
  • Journal Title: J Neurosci Res. 84(4) Pages: 874-90
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Formation of tauinclusions in knock-in mice with familial Alzheimer disease(FAD)mutation of presenilinl(PSl) (2006)
  • Author(s): Tanemura K, Chui DH, Nakano Y, Kudo T, Takeda M, Takashima A.
  • Journal Title: J Biol Chem. 281(8) Pages: 5037-41
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition of endocytosis activates alternative degradation pathway of・APP in cultured cells (2006)
  • Author(s): Fukumori A, Jiang J, Tanii H, Morihara T, Kamino K, Tanaka T, Kudo T, Itoh N, Tagami S, Okochi M, and Takeda M
  • Journal Title: Psychogeriatrics Sep 6 Pages: 107-113
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antipsychotic medication and cognitive function in schizophrenia (2006)
  • Author(s): Hori, H, Noguchi H, Hashimoto R, Nakabayashi T, Omori M, Tadahashi S, Tsukue R, Anami K, Hirabayashi N, Harada S, Saitoh O, Iwase M, Kajimoto O, Takeda M, Okabe S, Kungi H.
  • Journal Title: Schizophr Res 86 Pages: 138-146
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Discrepancy of performance among working memory related tasks in autism spectrum disorders was caused by task characteristics except working memory which could interfere with task execution (2006)
  • Author(s): Nakahachi T, Iwase M, Takahashi H, Honaga E, Sekipama R, Ukai S, Ishii, R, Ishigami W, Rajimoto O, Yamashita K, Hashimoto R, Shimizu A, Takeda M.
  • Journal Title: Psychiatry Clin Neurosci 60 Pages: 312-318
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Multiple anti-Alzheimer disease activities of non-steroidal anti-inflammatory drugs (2006)
  • Author(s): Morihara T, Cole GM, Tanii H, Tanaka T, Kudo T, Takeda M
  • Journal Title: Psychogeriatrics March;6(1) Pages: 1-3
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neurobiological studies of dementia-biological markers and neuroprotective strategies for Alzheimer disease (2006)
  • Author(s): Tanaka T, Isoe-Wada K, Yamamori H, Kato K, Nessa BN, Sadik GM, Takeda M.
  • Journal Title: Acta Neurol Taiwan 15 Pages: 68-71
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neurl substrates of emotionally valenced epidodec memory:A PET study using film stimuli (2006)
  • Author(s): Masaki Y, Nishikawa T, Ikejiri Y, Tokunaga H, Hatta N, Uema T, Kazui H, Doronbekov TK, Ogino A, Miyoshi N, Tanii H, Tanaka T, Oku N, Takeda M.
  • Journal Title: Psychiatry Clin Neurosci 60 Suppl 1 Pages: S46-51
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neural substrates of emotional habituation:A PET study using film stimuli (2006)
  • Author(s): Hatta N, Nishikawa T, Ikejiri Y, Tokunaga H, Masaki Y, Uema T, Kazui H, Doronbekov TK, Ogino A, Miyoshi N, Tanii H, Tanaka T, Oku N, Takeda M.
  • Journal Title: Psychiatry Clin Neurosci 60 Suppl 1 Pages: S40-45
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Toll-like receptor 3 mediated ρhyperphosphorylation of tau in human SH-SY5Y neuroblastoma cells (2006)
  • Author(s): Nessa BN, Tanaka T, Kamino K, Sadik G, Ansar AB, Kimura R, Tanii H, Okochi M, Morihara T, Tagami S, Kudo T, Takeda M.
  • Journal Title: Psychiatry Clin Neurosci. 60 Suppl 1 Pages: S27-33
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Biological markers for diagnosis of MCI and eurodegenerative dementia (2006)
  • Author(s): Takeda M, Kudo T, Tanaka T, Kamino K, Okochi M, Tagami S
  • Journal Title: Functional and Moleculart Imaging of Strokeka dn Dementia Pages: 101-107
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of valine on the efficiency and precision a cleavage of the Notch-1 transmembrane domain (2006)
  • Author(s): Tanii H, Jiang J, Fukumori A, Tagami S, Okazaki Y, Okochi M, and Takeda M
  • Journal Title: J Neurosci Res. Sep;84(4) Pages: 918-25
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of apoptosis and cholinergic dysfunction in ρAlzheimer's disease (2006)
  • Author(s): Tagami S, Tsujimoto Y, Akaike A, Takashima A, Hasegawa M, Ishiguro K, Shoji M, Ito N, Kanemaru K, Urakami K, Okochi M and Takeda M.
  • Journal Title: Psychogeriatrics Dec 6: Pages: S57-S63
  • 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 Jun2:344(2) Pages: 525-30
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] セクレターゼ阻害薬 (2006)
  • Author(s): 福森 亮雄, 田上 真次, 大河内 正康, 武田 雅俊
  • Journal Title: Pharma Medica Vol.24 No.7 Pages: 4
  • 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, Thhyama M, Tabira T, Takeda M.
  • Journal Title: Biochem Biophys Res Commun. 2 Pages: 344(2) : 525-30
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct. (2006)
  • Author(s): Fukumori A, Okochi M, Tagami S, Jiang J, Itoh N, Nakayama T, Yanagida K, Ishizuka-Katsura Y, Morihara Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A, Haass C, Takeda M.
  • Journal Title: Biochemistry. 18 Pages: 45(15) : 4907-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase. (2006)
  • Author(s): Yamasaki A, Eimer S, Okochi M, Smialowska A, Kaether C, Baumeister R, Haass C, Steiner H.
  • Journal Title: J Neurosci. 5 Pages: 26(14) : 3821-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Toll-like receptor 3 mediated hyperphosphorylation of tauin human SH-SY5Y neuroblastoma cells. (2006)
  • Author(s): Nessa BN, Tanaka T, Kamino K, Sadik G, Ansar AB, Kimura R, Tanii H, Okochi M, Morihara T, Tagami S, Kudo T, Takeda M.
  • Journal Title: Psychiatry Clin Neurosci. Apr60 Suppi 1 Pages: 527-33
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Development of new screening system for Alzheimer disease, in vitro Abeta sink assay, to identify the dissociation of soluble Abeta from fibrils. (2006)
  • Author(s): Sato N, Okochi M, Taniyama Y, Kurinami H, Shimamura M, Takeuchi D, Hamada H, Fukumori A, Kiyosue K, Taguchi T, Tanaka T, Miyasaka M, Takeda M, Ogihara T, Morishita R.
  • Journal Title: Neurobiol Dis. 22(3) Pages: 487-95
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Secretion of the Notch-1 Abeta-like peptide during Notch signaling. (2006)
  • Author(s): Okochi M, Fukumori A, Jiang J, Itoh N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M.
  • Journal Title: J Biol Chem. 24 Pages: 281(12) : 7890-8.
  • 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-beta in Alzheimer's disease. (2006)
  • Author(s): Nakamura K, Ohya W, Funakoshi H, Sakaguchi G Kato A, Takeda M. Kudo T, Nakamura T.
  • Journal Title: I Neurosci Res. 84(4) Pages: 874-90
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibition of endocytosis activates alternative degradation pathway of /3 APP in cultured cells. (2006)
  • Author(s): Fukumori A, Jiang J ; Tanii H, Morihara T, Kamino K, Tanaka T, Kudo T, Itoh N, Tagami S. Okochi M, Takeda M
  • Journal Title: Psychogeriatrics. Pages: 107-113
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antipsychotic medication and cognitive function in schizophrenia. (2006)
  • Author(s): Hon H, Noguchi H, Hashimoto R, Nakabayashi T, Omori Takahashi S, Tsukue R, Anami K, Hirabayashi N, Harada Saitoh O, Iwase M, Kajimoto 0, Takeda M, Okabe S, Kunugi H.
  • Journal Title: Schizophr Res 86 Pages: 138-146
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Multiple anti-Alzheimer disease activities of non-steroidal anti-inflammatory drugs. (2006)
  • Author(s): Moriliara 1', Cole GM, Tanii H, Tanaka T, Kudo T, Takeda M
  • Journal Title: Psychogeriatrics 6(1) Pages: 1-3
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neurobiological studies of dementia-biological markers and neuroprotective strategies for Alzheimer disease. (2006)
  • Author(s): Tanaka T, Isoe-Wada K, Yamamori H, Kato K, Nessa BN Sadik GM, Takeda M.
  • Journal Title: ActaNeurol Taiwan 15 Pages: 68-71
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] S46-51 Tanii H, Tanaka T, Oku N, Takeda M. Neural substrates of emotionally valenced episodic memory : A PET study using film stimuli. (2006)
  • Author(s): Masaki Y, Nishikawa T, Ikejiri Y, Tokunaga H, Haifa N, Uema T, Kazui H, Doronbekov TK, Ogino A, Miyoshi N.
  • Journal Title: Psychiatry Clin Neurosci(Suppl 1) 60
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] アミロイドβタンパク質産生の異常がアルツハイマー病につなが (2005)
  • Author(s): 大河内 正康
  • Journal Title: アルツハイマー病:治療の可能性を探る2005第.19回「大学と科学」公開シンポジウム講演抄録集 単行本 Pages: 13
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition of Aβ42 production by NSAIDS
  • Author(s): Okochi M, Tagami S, Takeda M
  • Journal Title: CURRENT THERAPY 24(3) Pages: 33-37
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Takashima A.Formation of tau inclusions in knock-in mice with familial Alzheimer disease(FAD) mutation of presenilin 1(PS1)
  • Author(s): Tanemura K, Chui DH,. Nakano Y, Kudo T, Takeda M, Takashima A.
  • Journal Title: J Biol Chem. 281(8) Pages: 5037-41
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Psychiatry Clin Neurosci Discrepancy of performance among working memory related tasks in autism spectrum disorders was caused by task characteristics except working memory which could interfere with task execution.
  • Author(s): Nakahachi T, Iwase M, Takahashi H, Honaga E, Sekiyama R, Ukai S. Ishii, R, Ishigami W, Kajimoto 0, Yamashita K, Hashimoto R Shimizu A, Takeda M.
  • Journal Title: Psychiatry Clin Neurosci 60 Pages: 312-318
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neural substrates of emotional habituation : A PET study using film stimuli.
  • Author(s): Hatta N, Nishikawa T, Ikejiri Y, Tokunaga H, Masaki Y, Uema T, Kazui H, Doronbekov TK, Ogino A, Miyoshi N, Tanii H, Tanaka T, Oku N, Takeda M.
  • Journal Title: Psychiatry Clin Neurosci(Suppl 1) 60 Pages: S40-45
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Biological markers for diagnosis of MCI and eurodegenerative dementia
  • Author(s): Takeda M, Kudo T, TanakaT, Karnino K, Okochi M, Tagami S
  • Journal Title: Functional and Moleculart Imaging of Strokeka dn Dementia Pages: 101-107
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of valine on the efficiency and precision at S4 cleavage of the Notch-1 transmembrane domain
  • Author(s): Tanii H, Jiang J, Fukumori A, Tagami S. Okazaki Y, Okochi M, Takeda M
  • Journal Title: J Neurosci Res. 84(4) Pages: 918-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of apoptosis and cholinergic dysfunction in Alzheimer's disease
  • Author(s): Tagami S, Tsujimoto Y, Akaike A, TakashimaA, Hasegawa M, Ishiguro K, Shoji M, Ito N, Kanemaru K, Urakami K Okochi M Takeda M.
  • Journal Title: Psychogeriatrics. 6 Pages: S57-S63
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 老年期認知症ナビゲーター (2006)
  • Author(s): 大河内 正康, 田上 真次, 武田 雅俊
  • Total Pages: 2
  • 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] 脳と循環 (2006)
  • Author(s): 大河内 正康, 田上 真次, 武田 雅俊
  • Total Pages: 13
  • 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