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

J Neurochem. 2003 Feb;84(4):864-77. doi: 10.1046/j.1471-4159.2003.01585.x.


Amyloid precursor protein (APP), the precursor of Abeta, 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 Abeta neurotoxicity. However, the relationship of APP-mediated neurotoxicity to JNK is not clear, partly because APP cytotoxicity is Abeta 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 Galphao, but not that of Galphai, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amyloid beta-Protein Precursor / antagonists & inhibitors
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Anthracenes / pharmacology
  • Antibodies / pharmacology
  • Carrier Proteins / pharmacology
  • Cell Death / drug effects
  • Cell Death / physiology*
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Genes, Dominant
  • Heterotrimeric GTP-Binding Proteins / genetics
  • Heterotrimeric GTP-Binding Proteins / metabolism
  • Hybrid Cells
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuroprotective Agents / pharmacology
  • Pertussis Toxin / pharmacology
  • Proteins / pharmacology


  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Protein Precursor
  • Anthracenes
  • Antibodies
  • Carrier Proteins
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Mapk8ip protein, mouse
  • Neuroprotective Agents
  • Proteins
  • humanin
  • pyrazolanthrone
  • Pertussis Toxin
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Heterotrimeric GTP-Binding Proteins