The lipidome associated with the γ-secretase complex is required for its integrity and activity

Biochem J. 2016 Feb 1;473(3):321-34. doi: 10.1042/BJ20150448.


γ-Secretase is a multi-subunit membrane protease complex that catalyses the final intramembrane cleavage of the β-amyloid precursor protein (APP) during the neuronal production of amyloid-β peptides (Aβ), which are implicated as the causative agents of Alzheimer's disease (AD). In the present study, we report the reconstitution of a highly purified, active γ-secretase complex into proteoliposomes without exogenous lipids and provide the first direct evidence for the existence of a microenvironment of 53 molecular species from 11 major lipid classes specifically associated with the γ-secretase complex, including phosphatidylcholine and cholesterol. Importantly, we demonstrate that the pharmacological modulation of certain phospholipids abolishes both the integrity and the enzymatic activity of the intramembrane protease. Together, our findings highlight the importance of a specific lipid microenvironment for the structure and function of γ-secretase.

Keywords: intramembrane-cleaving protease; lipid microenvironment; lipid species; mass spectrometry; proteoliposomes; quantitative shotgun lipidomics; γ-secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / chemistry*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Humans
  • Lipid Metabolism*
  • Proteolipids / chemistry
  • Proteolipids / metabolism*
  • Substrate Specificity


  • Amyloid beta-Protein Precursor
  • Proteolipids
  • proteoliposomes
  • Amyloid Precursor Protein Secretases