Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42

Biochemistry. 2004 Oct 26;43(42):13532-40. doi: 10.1021/bi049399k.


We previously showed that beta-amyloid precursor protein (APP) is cleaved not only in the middle of the membrane (gamma-cleavage) but also at novel cleavage sites close to the membrane/cytoplasmic boundary (epsilon-cleavage), releasing APP intracellular domains (AICDs) 49-99 and 50-99. To learn more about the relationship between gamma- and epsilon-cleavage, C-terminally truncated carboxyl-terminal fragments (CTFs) of APP, especially CTFs1-48 and 1-49 (the postulated products that are generated by epsilon-cleavage), were transiently expressed in CHO cells. Most importantly, the cells expressing CTF1-49 secreted predominantly amyloid beta-protein (Abeta) 40, while those expressing CTF1-48 secreted preferentially Abeta42. This supports our assumption that epsilon-cleavage precedes Alphabeta production and that preceding epsilon-cleavage determines the preference for the final Abeta species. The gamma-secretase inhibitors, L-685,458 and DAPT, suppressed Abeta production from CTF1-49. Regarding Abeta production from CTF1-48, L-685,458 suppressed it, but DAPT failed to do so. A dominant negative mutant of presenilin 1 suppressed the production of Abeta40 and 42 from both CTFs1-48 and 1-49. These data should shed significant light into the mechanism of Abeta production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / antagonists & inhibitors
  • Amyloid beta-Protein Precursor / biosynthesis
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • CHO Cells
  • Cricetinae
  • Endopeptidases / metabolism
  • Hydrolysis
  • Membrane Proteins / chemistry
  • Molecular Sequence Data
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Presenilin-1
  • Protease Inhibitors / chemistry
  • Protein Processing, Post-Translational*
  • Sequence Deletion*
  • Substrate Specificity
  • Transfection


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • Peptide Fragments
  • Presenilin-1
  • Protease Inhibitors
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases
  • Endopeptidases