Mechanism of cytotoxicity mediated by the C31 fragment of the amyloid precursor protein

Biochem Biophys Res Commun. 2009 Oct 16;388(2):450-5. doi: 10.1016/j.bbrc.2009.08.042. Epub 2009 Aug 11.

Abstract

The cytoplasmic tail of the amyloid precursor protein (APP) contains two putatively cytotoxic peptides, Jcasp and C31, derived by caspase cleavage of APP. Jcasp is a fragment starting from the epsilon-secretase site to position 664, while C31 is a fragment from position 665 to the C-terminus. Our studies now showed that compared to C31, Jcasp appeared to play a minor role in cytotoxicity. In particular, inhibition of Jcasp generation by treatment of gamma-secretase inhibitor did not lead to any attenuation of C31-induced toxicity. Secondly, because C31 toxicity is largely absent in cells lacking endogenous APP, we determined, using a split beta-galactosidase complementary assay to monitor protein-protein interactions, the presence of APP associated complexes. Our results demonstrated that both APP homomeric and C31/APP heteromeric complexes were correlated with cell death, indicating that C31 complexes with APP to recruit the interacting partners that initiate the signals related to cellular toxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / biosynthesis*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Apoptosis
  • Aspartic Acid / genetics
  • Cell Line, Tumor
  • Cytotoxins / biosynthesis*
  • Cytotoxins / genetics
  • Dipeptides / pharmacology
  • Mice
  • Molecular Sequence Data
  • Peptide Fragments / biosynthesis*
  • Peptide Fragments / genetics
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Rats

Substances

  • Amyloid beta-Protein Precursor
  • Cytotoxins
  • Dipeptides
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Peptide Fragments
  • Aspartic Acid
  • Amyloid Precursor Protein Secretases