Degradation of amyloid-beta

• Project/Area Number: 16591132
• 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, Department of Post-Genomics and Diseases, Assistant, 医学系研究科, 助手 (40362735)
• Co-Investigator(Kenkyū-buntansha): OKOCHI Masayasu Osaka University, Graduate School of Medicine, Department of Post-Genomics and Diseases, Assistant, 医学系研究科, 助手 (90335357) ; TAKEDA Masatoshi Osaka University, Graduate School of Medicine, Department of Post-Genomics and Diseases, Professor, 医学系研究科, 教授 (00179649)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: BACE / Aβ degradation / γ-secretase / cell-free BACE assay / cell-free BACE assay

Research Abstract

Senile plaque is a pathological hallmark of Alzheimer's disease (AD) and its major component is amyloid-beta peptides (Aβ). Either inhibition of Aβ generation or enhancement of Aβ degradation is fundamental approach in developing effective ways to cure AD. We revealed that beta-secretase, which sheds beta-amyloid protein precursor (βAPP) to generate CTF-β, truncates Aβ at two sites. Interestingly, truncated Aβ aggregated much slower than full length Aβ, thus the truncation of Aβ by BACE may promote Aβ degradation. BACE may be utilized as Aβ degrading enzyme if the activity to shed βAPP is selectively inhibited somehow. Moreover, we showed that Aβ peptide inhibited BACE activity at least in vitro. This suggested that Aβ may inhibit BACE activity, which in turn reduces Aβ production. We propose that there might be negative feedback mechanism in Aβ generation cascade.

Research Products

• [Journal Article] Secretion of the Notch-1 Aβ-like peptide during Notch signaling. (2006)
  • Author(s): Okochi M, Fukumori A, Jiang J, Ito N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M.
  • Journal Title: J Biol Chem. 281.12 Pages: 7890-7898
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Presenilin-dependent γ-secretase on plasma membrane and endoso mes 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 Pages: 5351-5358
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Secretion of the Notch-1 Aβ-like peptide during Notch signaling. (2006)
  • Author(s): Okochi M, Fukumori A, Jiang J, Ito N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M.
  • Journal Title: J Biol Chem 281-12 Pages: 7890-7898
  • 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): 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 Pages: 5351-5358
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Secretion of the Notch-1 Aβ-like peptide during Notch signaling. (2006)
  • Author(s): Okochi M, Fukumori A, Jiang J, Ito N, Kimura R, Steiner H, Haass C, Tagami S, Takeda M.
  • Journal Title: J Biol Chem. 3月予定(In press)
• [Journal Article] The S3 cleavage site of Notch-1 by presenilin/γ-secretase has a diversity. (2005)
  • Author(s): Tagami S, Okochi M, Fukumori A, Ito N, Jiang J, Ikuta A, Takeda M.
  • Journal Title: 日本神経化学雑誌 44 Pages: 204-204
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] プレセニリン依存性膜内蛋白分解によるNotch-1のS3切断には多様性が存在する。 (2005)
  • Author(s): Tagami S, Okochi M, Fukumori A, Ito N, Jiang J, Ikuta A, Kudo T, Takeda M.
  • Journal Title: Dementia Japan 19 Pages: 133-133
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The physiological meaning that BACE cleaves amyloid beta. (2005)
  • Author(s): Tagami S, Okochi M, Fukumori A, Ito N, Jiang J, Ikuta A, Kudo T, Takeda M.
  • Journal Title: Joint meeting of the 27th annual meeting of JSBP and the 35th annual meeting of JSNP 27 Pages: 206-206
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] γセクレターゼとNotchシグナル (2005)
  • Author(s): 大河内正康, 田上真次, 武田雅俊
  • Journal Title: Molecular Medicine 42 Pages: 790-798
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The S3 cleavage site of Notch-1 by presenilin/γ-secretase has a diversity. (2005)
  • Author(s): Tagami S, Okochi M, Fukumori A, Ito N, Jiang J, Ikuta A, Takeda M.
  • Journal Title: Bulletin of the Japanese Society for Neurochemistry 44 Pages: 204-204
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cleavage at S3 by Presenilin/g-secretase has a diversity. (2005)
  • Author(s): Tagami S, Okochi M, Fukumori A, Ito N, Jiang J, Ikuta A, Kudo T, Takeda M.
  • Journal Title: Dementia Japan 19 Pages: 133-133
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aβの毒性発現機構 (2004)
  • Author(s): 大河内正康, 田上真次, 武田雅俊
  • Journal Title: Molecular Medicine 41.No.4 Pages: 427-431
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Subcellular localization of γ-cleavage of βAPP. (2004)
  • Author(s): Fukumori, A., Okochi, M., Jiang, J., Kimura, R., Tanii, H., Kudo, T., Tagami, S., Takeda, M
  • Journal Title: 日本神経化学雑誌 47 Pages: 20-20
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The mechanism of intracellular amyloid beta degradation (2004)
  • Author(s): Tagami, S., Okochi, M., Fukumori, A., Kimura, R., Jiang, J., Takeda, M
  • Journal Title: 9th International Conference on Alzheimer's Disease and Related Disorders Abstract Book 9巻 Pages: 97-97
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Biochemical separation of γ-cleavage of βAPP on the plasma membrane from that on the intracellular membrane (2004)
  • Author(s): Fukumori, A., Okochi, M., Tagami, S, Tanii, H., Kimura, R., Jiang, J., Steiner, H., Haass, C., Kudo, T., Takeda, M.
  • Journal Title: 9th International Conference on Alzheimer's Disease and Related Disorders Abstract Book 9巻 Pages: 157-157
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The mechanism of intracellular amyloid beta degradation (2004)
  • Author(s): Tagami, S., Okochi, M., Fukumori, A., Kimura, R., Jiang, J., Takeda, M
  • Journal Title: 9th International Conference on Alzheimer's Disease and Related Disorders Abstract Book 9 Pages: 97-97
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Biochemical separation of γ-cleavage of βAPP on the plasma membrane from that on the intracellular membrane (2004)
  • Author(s): Fukumori, A., Okochi, M., Tagami, S., Tanii, H., Kimura, R., Jiang, J., Steiner, H., Haass, C., Kudo, T., Takeda, M.
  • Journal Title: 9th International Conference on Alzheimer's Disease and Related Disorders Abstract Book 9 Pages: 157-157
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aβの毒性発現機構 (2004)
  • Author(s): 大河内正康, 田上真次, 武田雅俊
  • Journal Title: Molecular Medicine 41-No.4 Pages: 427-431
• [Journal Article] Subcellular localization of γ-cleavage of βAPP. (2004)
  • Author(s): Fukumori, A., et al.
  • Journal Title: 日本神経化学雑誌 47 Pages: 20-20
• [Journal Article] The mechanism of intracellular amyloid beta degradation (2004)
  • Author(s): Tagami, S., et al.
  • Journal Title: 9th International Conference on Alzheimer's Disease and Related Disorders Abstract Book 9巻 Pages: 97-97
• [Journal Article] Biochemical separation of γ-cleavage of βAPP on the plasma membrane from that on the intracellular membrane. (2004)
  • Author(s): Fukumori, A., et al.
  • Journal Title: 9th International Conference on Alzheimer's Disease and Related Disorders Abstract Book 9巻 Pages: 157-157
• [Book] 研修医の精神科研修ハンドブック (2005)
  • Author(s): 田上真次, 武田雅俊
  • Total Pages: 8
  • Publisher: アルツハイマー型痴呆
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 痴呆とうつ 心療内科 (2005)
  • Author(s): 田上真次, 大河内正康, 武田雅俊
  • Publisher: 科学評論社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 研修医の精神科研修ハンドブック(アルツハイマー型痴呆) (2005)
  • Author(s): 田上 真次, 武田 雅俊
  • Total Pages: 8