Alternative pathways for production of beta-amyloid peptides of Alzheimer's disease

Biol Chem. 2008 Aug;389(8):993-1006. doi: 10.1515/BC.2008.124.


This highlight article describes three Alzheimer's disease (AD) studies presented at the 5th General Meeting of the International Proteolysis Society that address enzymatic mechanisms for producing neurotoxic beta-amyloid (Abeta) peptides. One group described the poor kinetics of BACE 1 for cleaving the wild-type (WT) beta-secretase site of APP found in most AD patients. They showed that cathepsin D displays BACE 1-like specificity and cathepsin D is 280-fold more abundant in human brain than BACE 1. Nevertheless, as BACE 1 and cathepsin D show poor activity towards the WT beta-secretase site, they suggested continuing the search for additional beta-secretase(s). The second group reported cathepsin B as an alternative beta-secretase possessing excellent kinetic efficiency and specificity for the WT beta-secretase site. Significantly, inhibitors of cathepsin B improved memory, with reduced amyloid plaques and decreased Abeta(40/42) in brains of AD animal models expressing amyloid precursor protein containing the WT beta-secretase site. The third group addressed isoaspartate and pyroglutamate (pGlu) posttranslational modifications of Abeta. Results showed that cathepsin B, but not BACE 1, efficiently cleaves the WT beta-secretase isoaspartate site. Furthermore, cyclization of N-terminal Glu by glutaminyl cyclase generates highly amyloidogenic pGluAbeta(3-40/42). These presentations suggest cathepsin B and glutaminyl cyclase as potential new AD therapeutic targets.

Publication types

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

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Peptides / genetics
  • Animals
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Peptide Fragments / biosynthesis*
  • Peptide Fragments / genetics
  • Substrate Specificity


  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Peptide Fragments
  • Amyloid Precursor Protein Secretases