Secretase inhibitors for Alzheimer's disease: challenges of a promiscuous protease

Curr Opin Investig Drugs. 2005 Jan;6(1):35-47.


The proteolytic enzyme gamma-secretase cleaves amyloid precursor protein (beta-APP), following beta-secretase cleavage to generate the amyloid-beta peptides that are causally linked to Alzheimer's disease (AD). However, gamma-secretase is also responsible for intramembranous cleavage of a growing list of additional transmembrane proteins, and therefore therapeutic inhibition of gamma-secretase might also affect these substrates. Such blockade over a chronic period may be deleterious, due to interference with potential cell signaling pathways activated by any of the products of these novel gamma-secretase substrates. In addition, inhibition of gamma-secretase leads to alterations in other beta-APP metabolites, with potential toxicity and signaling implications. The potential consequences of these off-target effects of gamma-secretase inhibitors are reviewed.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Aspartic Acid Endopeptidases
  • Endopeptidases / metabolism*
  • Humans
  • Ligands
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use*
  • Substrate Specificity


  • Amyloid beta-Protein Precursor
  • Ligands
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human