Assembly, trafficking and function of gamma-secretase

Neurodegener Dis. 2006;3(4-5):275-83. doi: 10.1159/000095267.


Gamma-secretase catalyzes the final cleavage of the beta-amyloid precursor protein to generate amyloid-beta peptide, the principal component of amyloid plaques in the brains of patients suffering from Alzheimer's disease. Here, we review the identification of gamma-secretase as a protease complex and its assembly and trafficking to its site(s) of cellular function. In reconstitution experiments, gamma-secretase was found to be composed of four integral membrane proteins, presenilin (PS), nicastrin (NCT), PEN-2 and APH-1 that are essential and sufficient for gamma-secretase activity. PS, which serves as a catalytic subunit of gamma-secretase, was identified as a prototypic member of novel aspartyl proteases of the GxGD type. In human cells, gamma-secretase could be further defined as a heterogeneous activity consisting of distinct complexes that are composed of PS1 or PS2 and APH-1a or APH-1b homologues together with NCT and PEN-2. Using green fluorescent protein as a reporter we localized PS and gamma-secretase activity at the plasma membrane and endosomes. Investigation of gamma-secretase complex assembly in knockdown and knockout cells of the individual subunits allowed us to develop a model of complex assembly in which NCT and APH-1 first stabilize PS before PEN-2 assembles as the last component. Furthermore, we could map domains in PS and PEN-2 that govern assembly and trafficking of the complex. Finally, Rer1 was identified as a PEN-2-binding protein that serves a role as an auxiliary factor for gamma-secretase complex assembly.

Publication types

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

MeSH terms

  • Alzheimer Disease / enzymology
  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Humans
  • Protein Structure, Quaternary / physiology*
  • Protein Transport


  • Amyloid Precursor Protein Secretases