Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death

Yuichi Hashimoto, Osahiko Tsuji, Takako Niikura, Yohichi Yamagishi, Miho Ishizaka, Masaoki Kawasumi, Tomohiro Chiba, Kohsuke Kanekura, Marina Yamada, Emi Tsukamoto, Keisuke Kouyama, Kenzo Terashita, Sadakazu Aiso, Anning Lint, Ikuo Nishimoto

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82 Citations (Scopus)

Abstract

Amyloid precursor protein (APP), the precursor of Aβ, has been shown to function as a cell surface receptor that mediates neuronal cell death by anti-APP antibody. The c-Jun N-terminal kinase (JNK) can mediate various neurotoxic signals, including Aβ neurotoxicity. However, the relationship of APP-mediated neurotoxicity to JNK is not clear, partly because APP cytotoxicity is Aβ independent. Here we examined whether JNK is involved in APP-mediated neuronal cell death and found that: (i) neuronal cell death by antibody-bound APP was inhibited by dominant-negative JNK, JIP-1b and SP600125, the specific inhibitor of JNK, but not by SB203580 or PD98059; (ii) constitutively active (ca) JNK caused neuronal cell death and (iii) the pharmacological profile of caJNK-mediated cell death closely coincided with that of APP-mediated cell death. Pertussis toxin (PTX) suppressed APP-mediated cell death but not caJNK-induced cell death, which was suppressed by Humanin, a newly identified neuroprotective factor which inhibits APP-mediated cytotoxicity. In the presence of PTX, the PTX-resistant mutant of Gαo, but not that of Gαi, recovered the cytotoxic action of APP. These findings demonstrate that JNK is involved in APP-mediated neuronal cell death as a downstream signal transducer of Go.

Original languageEnglish
Pages (from-to)864-877
Number of pages14
JournalJournal of Neurochemistry
Volume84
Issue number4
DOIs
Publication statusPublished - 2003 Feb 1

Keywords

  • Alzheimer's amyloid precursor protein
  • Antiamyloid precursor protein antibody
  • C-Jun N-terminal kinase
  • G protein
  • Humanin
  • Neuronal death

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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  • Cite this

    Hashimoto, Y., Tsuji, O., Niikura, T., Yamagishi, Y., Ishizaka, M., Kawasumi, M., Chiba, T., Kanekura, K., Yamada, M., Tsukamoto, E., Kouyama, K., Terashita, K., Aiso, S., Lint, A., & Nishimoto, I. (2003). Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death. Journal of Neurochemistry, 84(4), 864-877. https://doi.org/10.1046/j.1471-4159.2003.01585.x