Dependency of γ-secretase complex activity on the structural integrity of the bilayer.

γ-secretase is a membrane protein complex associated with the production of Aβ peptides that are pathogenic in Alzheimer's disease. We have characterized the activity of γ-secretase complexes under a variety of detergent solubilization and reconstitution conditions, and the structural state of proteoliposomes by electron microscopy. We found that γ-secretase activity is highly dependent on the physical state or integrity of the membrane bilayer--partial solubilization may increase activity while complete solubilization will abolish it. The activity of well-solubilized γ-secretase can be restored to near native levels when properly reconstituted into a lipid bilayer environment.