Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex

Neuron. 2003 Apr 10;38(1):9-12. doi: 10.1016/s0896-6273(03)00205-8.


Gamma-Secretase cleaves the Amyloid Precursor Protein (APP) in its transmembrane domain, releasing the amyloid peptide Abeta. Abeta is the main constituent of the amyloid plaques in the brains of patients suffering from Alzheimer's disease. Several other type I integral membrane proteins are also cleaved by this protease. Recent work indicates that gamma-Secretase is a multiprotein complex consisting of Presenilin, Nicastrin, Aph-1, and Pen-2 and that all four proteins are necessary for full proteolytic activity. Since several paralogs and alternatively spliced variants of at least Presenilin and Aph-1 have been identified as well, it is anticipated that gamma-Secretase is not a homogeneous activity. Gamma-Secretase is an interesting but complex drug target that challenges classical thinking about proteolytic processing and intracellular signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Endopeptidases / metabolism*
  • Humans
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / metabolism*
  • Peptide Hydrolases
  • Presenilin-1
  • Presenilin-2
  • Protein Binding


  • Membrane Glycoproteins
  • Membrane Proteins
  • PSEN1 protein, human
  • PSEN2 protein, human
  • PSENEN protein, human
  • Presenilin-1
  • Presenilin-2
  • nicastrin protein
  • APH1A protein, human
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Peptide Hydrolases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human