Characterization of BACE-mediated proteolysis including amyloid-beta

• Project/Area Number: 18591285
• 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: TAGAMI Shinji Osaka University, Graduate School of Medicine, Assistant Professor (40362735)
• Co-Investigator(Kenkyū-buntansha): OKOCHI Masayasu Osaka Univetsty, Graduate School of Medicine, Assistant Professor (90335357) ; TAKEDA Masatoshi Osaka Univetsty, Graduate School of Medicine, Professor (00179649)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,880,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥480,000); Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: BACE / Presenilin / gamma secretase / amvloid beta / Alzheimer disease

Research Abstract

Senile plaque is a pathological hallmark of Alzheimer's disease (AD) and its major component is amyloid-beta 42(Aβ42). Inhibition of Aβ generation or enhancement of Aβ degradation is fundamental approach in developing methods to treat AD. We revealed that BACE, which sheds beta-amyloid protein precursor (βAPP) to generate CTF-13, truncates Aβ at least two sites. Interestingly, truncated Aβ aggregated much slower than full length Aβ, thus the truncation of Aβ by BACE may promote Aβ degradation. Importantly, BACE also truncated highly aggregatable, pathogenic Aβ42. Based on mutagenesis of BACE1, we tried to obtain BACE mutants which truncate Aβ bun do not shed βAPP. We finally found that BACE1 of which the transmembrane domain is deleted maintained Aβ degrading activity, while it did not shed bAPP. Therefore, introduction of such an enzyme may be used to enhance pathogenic Aβ species

Research Products

• [Journal Article] Regulation of Notch signaling by dynamic changes in the precision in S3 cleavage of Notch-1 (2008)
  • Author(s): Tagami S, Okochi M, Yanagida K, Ikuta A, Fukumori A, Matsumoto N, Ishizuka-Katsura Y, Nakayama T, Itoh N, Jiang J, Nishitomi K, Kamino K, Morihara T, Hashimoto R, Tanaka T, Kudo T, Chiba S, Takeda M.
  • Journal Title: Molecular and Cellular Biology. 28 Pages: 165-176
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Processes of beta-amyloid and intracellular cytoplasmic domain generation by presenilin/gamma-secretase. (2008)
  • Author(s): Tagami S, Okochi M, Fukumori A, Jiang J, Yanagida K, Nakayama T, Morihara T, Tanaka T, Kudo T, Takeda M.
  • Journal Title: Neurodegenerative Diseases 5 Pages: 160-162
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Regulation of Notch signaling by dynamic changes in the precision in S3 cleavage of Notch-1 (2008)
  • Author(s): Tagami, S, Okochi, M, Yanagida, K, Ikuta, A, Fukumori, A, Matsumoto, N, Ishizuka-Katsura, Y Nakayama, T, Itoh, N, Jiang, J, Nishitomi, K, Kamino, K, Morihara, T, Hashimoto, R, Tanaka, T, Kudo, T, Chiba, S, Takeda, M
  • Journal Title: Molecular and Cellular Biology. Jan 28 Pages: 165-176
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Processes of beta-amyloid and intracellular cytoplasmic domaingeneration by presenili n/gamma-secretase (2008)
  • Author(s): Tagami, S, Okochi, M, Fukumori, A, Jiang, J, Yanagida, K, Nakayama, T, Morihara, T, Tanaka, T, Kudo, T, Takeda, M
  • Journal Title: Neurodegenerative Diseases 5 Pages: 160-162
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of Notch signaling by dynamic changes in the precision in S3 cleavage of Notch-1 (2008)
  • Author(s): Tagami S. Okochi M, Yanagida K, Ikuta A, Fukumori A, Matsumoto N, Ishizuka-Katsura Y, Nakayama T, Itoh N, Jiang J, Nishitomi K, Kamino K, Morihara T, Hashimoto R, Tanaka T, Kudo T, Chiba S, Takeda M.
  • Journal Title: Molecular and Cellular Biology. 28 Pages: 165-176
  • Peer Reviewed
• [Journal Article] Biological markers as outcome measures for Alzheimer's disease interventions-real problems and future possibilities. (2007)
  • Author(s): Takeda M, Okochi M, Tagami S, Tanaka T, Kudo T.
  • Journal Title: International Psychogeriatrics 19 Pages: 391-400
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Biological markers as outcome measures for Alzheimer's disease interventions-real problems and future possibilities (2007)
  • Author(s): Takeda, M, Okochi, M, Tagami, S, Tanaka, T, Kudo, T
  • Journal Title: Int Psychogeriatr 19 Pages: 391-400
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Biological markers as outcome measures for Alzheimer's disease interventions-real problems and future possibilities. (2007)
  • Author(s): Takeda M, Okochi M, Tagami S. Tanaka T, Kudo T.
  • Journal Title: Int Psychogeriatr. 19 Pages: 391-400
  • Peer Reviewed
• [Journal Article] Involvement of apoptosis and cholinergic dysfunction in Alzheimer'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 SUPPL.2
  • NAID: 10025860692
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Effect of valine on the efficiency and precision at S4 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: Journal of Neuroscience Research 84 Pages: 918-925
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Inhibition of endocytosis activates alternative degradati on pathway of βAPP 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 6 Pages: 107-113
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Aβ induces endoplasmic reticulum stress causing possible proteasome impairment via the endoplasmic reticulum-associated degradation pathway. (2006)
  • Author(s): .Kanayama D, T, Kudo, Kimura R, Tabuchi N, Fukumori A, Morihara T, Tagami S, Tanii H, Okochi M, Kamino K, Tanaka T, Imaizumi K, Tabira T, and Takeda M.
  • Journal Title: Psychogeriatrics 6 Pages: 100-106
  • NAID: 10019375777
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [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, and Takeda M.
  • Journal Title: Biochem Diophys Res Commun 344 Pages: 525-530
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Toll-like receptor 3 mediated hyperphosphorylation 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 Suppl 1
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Involvement of apoptosis and cholinergic dysfunction in Alzheimer'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, Takeda, M
  • Journal Title: Psychogeriatrics 6 : (SUPPL.2)
  • NAID: 10025860692
  • 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- (2006)
  • 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] Inhibition of endocytosis activates alternative degradation pathway of CAPP in cultured cells (2006)
  • Author(s): Fukumori, A, Jiang, J, Tanii, H, Morihara, T, Kamino, K, Tanaka, T, Kudo, T, Itoh, N, Tagami, 5, Okochi, M, Takeda, M
  • Journal Title: Psychogeriatrics 6 Pages: 107-113
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Toll-like receptor 3 mediated hyperphosphorylation 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: PsychiatryClin Neurosci 60 Suppl 1 Pages: 27-33
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ab induces endoplasmic reticulum stress causing possible proteasome impairment via the endoplasmic reticulum-associated degradation pathway (2006)
  • Author(s): Kanayama, D, T, Kudo, Kimura, R, Tabuchi, N, FukumoriA, Morihara, T, Tagami, S, Tanii, H, Okochi, M, Kamino, K, Tanaka, T, Imaizumi, K, Tabira, T, Takeda, M
  • Journal Title: Psychogeriatrics 6 Pages: 100110-100110
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Altered localization of amyloid precursor protein under endoplasmis 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, Fukumiri, A, Tagami, S, Okochi, M, Kubo, M, Tanii, H, Tohyama, M, Tabira, T, Takeda, M
  • Journal Title: Biochem Diophys Res Commun 344 Pages: 525-530
  • 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 T, Kamino K, Tanaka T, Kudo T, Tanii H, Ikuta A, Haass C, Takeda M.
  • Journal Title: Biochemistry Apr 18;45(15) Pages: 4907-4914
• [Journal Article] Involvement of apoptosis and cholinergic dysfunction in Alzheimer'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, Takeda M.
  • Journal Title: Psychogeriatrics Dec 6:(SUPPL.2)
  • NAID: 10025860692
• [Journal Article] Effect of valine on the efficiency and precision at S4 cleavage of the Notch-1 transmembrane domain. (2006)
  • Author(s): Tanii H, Jiang J, Fukumori A, Tagami S, Okazaki Y, Okochi M, Takeda M.
  • Journal Title: J Neurosci Res Sep;84(4) Pages: 918-925
• [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. Jun 2;344(2)
• [Journal Article] Toll-like receptor 3 mediated hyperphosphorylation 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. Apr;60
• [Presentation] Regulation of Notch signaling by dynamic changes in the precision in S3 cleavage of Notch-1. (2007)
  • Author(s): Tagami, S., Okochi, M., Nakayama T., Jiang J., Nishitomi K., Mori K., Fukumori A., Yanagida K., and Takeda, M.
  • Organizer: 37th Neoroscience Meeting
  • Place of Presentation: San Diego Convention Center Room 28E
  • Year and Date: 2007-11-05
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Regulation of Notch signaling by dynamic changes in the precision in S3 cleavage of Notch-1 (2007)
  • Author(s): Tagami, S., Okochi, M., Nakayama, T., Jiang, J., Nishitomi, K., Mori, K., Fukumori, A., Yanagida, K., Takeda, M
  • Organizer: 37th Neoroscience Meeting
  • Place of Presentation: San Diego Convention Center Room 28E
  • Year and Date: 2007-11-05
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Dynamic regulation of Notch signaling by presenilin/γ-secretase (2007)
  • Author(s): Tagami, S., Okochi, M., and Takeda M.
  • Organizer: The 13th Congress of International Psychogeriatric Association
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2007-10-18
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Dynamic regulation of Notch signaling by presenilin/y-secretase (2007)
  • Author(s): Tagami, S., Okochi, M., Takeda, M
  • Organizer: The 13th Congress of International Psychogeriatric Association
  • Place of Presentation: Osaka International Congress Hall
  • Year and Date: 2007-10-18
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Changes in a precision of S3 cleavage by presenilin/y-secretase regulate Notch signaling (2007)
  • Author(s): Tagami, S., Okochi, M., Nakayama, T., Jiang, J., Nishitomi, K., Mori, K., Fukumori, A., Yanagida, K., Takeda, M
  • Organizer: The 13th Congress of International Psychogeriatric Association
  • Place of Presentation: Osaka International Congress Hall
  • Year and Date: 2007-10-18
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Enhancement ofAbeta degradation by BACE1 (2007)
  • Author(s): Tagami, S., Okochi, M., Nakayama, T., Jiang, J., Nishitomi, K., Mori, K., Fukumori, A., Yanagida, K., Takeda, M
  • Organizer: The 13th Congress of International Psychogeriatric Association
  • Place of Presentation: Osaka International Congress Hall
  • Year and Date: 2007-10-18
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation of Notch signaling by a novel S3 cleavage diversity (2007)
  • Author(s): 田上真次 大河内正康 柳田寛太 生田亜希子 福森亮雄 森康治 姜 経緯 西冨晃平 小栗崇史 中山泰亮 武田雅俊
  • Organizer: 第29回日本生物学的精神医学会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2007-07-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Regulation of Notch signaling by a novel S3 cleavage diversity (2007)
  • Author(s): Tagami, S., Okochi, M., Nakayama, T., Jiang, J., Nishitomi, K., Mori, K., Fukumori, A., Yanagida, K., Takeda, M
  • Organizer: 29th JSBP
  • Place of Presentation: Sapporo convention center
  • Year and Date: 2007-07-12
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Changes in a precision of S3 cleavage by presenilin/γ-secretaseregulate Notch signaling. (2007)
  • Author(s): Tagami, S., Okochi, M., Nakayama T., Jiang J., Nishitomi K., Mori K., Fukumori A., Yanagida K., and Takeda, M.
  • Organizer: The 13th Congress of International Psychogeriatric Association
  • Place of Presentation: 大阪国際会議場
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Enhancement of Abeta degradation by BACE1. (2007)
  • Author(s): Tagami, S., Okochi, M., Nakayama T., Jiang J., Nishitomi K., Mori K., Fukumori A., Yanagida K., and Takeda, M.
  • Organizer: The 13th Congress of International Psychogeriatric Association
  • Place of Presentation: 大阪国際会議場
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Changes in a precision of S3 cleavage by presenilin/γ-secretase regulate Notch signaling. (2007)
  • Author(s): Tagami, S., Okochi, M., Nakayama T., Jiang J., Nishitomi K., Mori K., Fukumori A., Yanagida K., and Takeda, M.
  • Organizer: The 13th Congress of International Psychogeriatric Association
  • Place of Presentation: 大阪国際会議場
• [Presentation] Effects of multiple factors including γ-secretase modifiers on the precision of Presenilin-dependent intramambranous proteolysis. (2006)
  • Author(s): 田上真次 大河内正康 福森亮雄 姜 経緯 森康治 中山泰亮 生田亜希子 桂芳子 小栗崇史 西冨晃平 伊藤尚弘 柳田寛太 武田雅俊
  • Organizer: 第25回日本認知症学会大会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2006-10-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Effects of multiple factors including y-secretase modifiers on the precision of Presenilin-dependent intramambranous proteolysis (2006)
  • Author(s): Tagami, S., Okochi, M., Nakayama, T., Jiang, J., Nishitomi, K., Mori, K., Fukumori, A., Yanagida, K., Takeda, M
  • Organizer: 25th JSDR
  • Place of Presentation: Nagoya convention center
  • Year and Date: 2006-10-06
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation of Notch signaling by presenilin/□-secretase (2006)
  • Author(s): 田上真次 大河内正康 福森亮雄 姜 経緯 森康治 中山泰亮 生田亜希子 桂芳子 小栗崇史 西冨晃平 伊藤尚弘 柳田寛太 武田雅俊
  • Organizer: 第49回日本神経化学会大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2006-09-14
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Regulation of Notch signaling by presenilin/y-secretase (2006)
  • Author(s): Tagami, S., Okochi, M., Fukumori, A., Takeda, M
  • Organizer: 49th JNC
  • Place of Presentation: Nagoya convention center
  • Year and Date: 2006-09-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Comparison of S3 cleavage of Notch-1 with ε-cleavage of βAPP by presenilin/γ-secretase (2006)
  • Author(s): Shinji Tagami, Masayasu Okochi, Akio Fukumori, and Masatoshi Takeda
  • Organizer: The 10th International Conference on Alzheimer's disease and Related Disorders
  • Place of Presentation: IFEMA Feria de Madrid, Spain
  • Year and Date: 2006-07-18
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Comparison of S3 cleavage of Notch-1 withy-cleavage of BAPP by presenilin/y-secretase (2006)
  • Author(s): Tagami, S., Okochi, M., Fukumori, A., Takeda, M
  • Organizer: The 10th International Conference on Alzheimer's disease and Related Disorders
  • Place of Presentation: IFEMA Feria de Madrid, Spain
  • Year and Date: 2006-07-18
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 第10回国際アルツハイマー病学会に参加して学会印象記 (2008)
  • Author(s): 田上真次
  • Total Pages: 18
  • Publisher: Psychiatry Today
• [Book] アンチエイジングと精神医学 (2007)
  • Author(s): 田上真次, 大河内正康, 武田雅俊
  • Publisher: Journal of Otolaryngology, Head and Neck Surgery東京医学社
• [Book] BACEによるアミロイドベータ蛋白の切断について (2006)
  • Author(s): 田上真次, 大河内正康, 武田雅俊ほか
  • Total Pages: 230
  • Publisher: 精神薬療研究年報 第38集