Cathepsin L Mediates the Degradation of Novel APP C-Terminal Fragments

Biochemistry. 2015 May 12;54(18):2806-16. doi: 10.1021/acs.biochem.5b00329. Epub 2015 Apr 28.


Alzheimer's disease (AD) is characterized by the deposition of amyloid β (Aβ), a peptide generated from proteolytic processing of its precursor, amyloid precursor protein (APP). Canonical APP proteolysis occurs via α-, β-, and γ-secretases. APP is also actively degraded by protein degradation systems. By pharmacologically inhibiting protein degradation with ALLN, we observed an accumulation of several novel APP C-terminal fragments (CTFs). The two major novel CTFs migrated around 15 and 25 kDa and can be observed across multiple cell types. The process was independent of cytotoxicity or protein synthesis. We further determine that the accumulation of the novel CTFs is not mediated by proteasome or calpain inhibition, but by cathepsin L inhibition. Moreover, these novel CTFs are not generated by an increased amount of BACE. Here, we name the CTF of 25 kDa as η-CTF (eta-CTF). Our data suggest that under physiological conditions, a subset of APP undergoes alternative processing and the intermediate products, the 15 kDa CTFs, and the η-CTFs aret rapidly degraded and/or processed via the protein degradation machinery, specifically, cathepsin L.

Publication types

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

MeSH terms

  • Amyloid Precursor Protein Secretases / biosynthesis
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Calpain / antagonists & inhibitors
  • Cathepsin L / antagonists & inhibitors
  • Cathepsin L / metabolism*
  • Cattle
  • Cell Line, Tumor
  • Cells, Cultured
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • Leupeptins / pharmacology
  • Peptide Fragments / metabolism
  • Proteolysis
  • Rats
  • Ubiquitination


  • Amyloid beta-Protein Precursor
  • Leupeptins
  • Peptide Fragments
  • acetylleucyl-leucyl-norleucinal
  • L-Lactate Dehydrogenase
  • Amyloid Precursor Protein Secretases
  • Calpain
  • Cathepsin L