gamma-secretase is a membrane protein complex associated with the production of All peptides that are pathogenic in Alzheimer's disease. We have characterized the activity of gamma-secretase complexes under a variety of detergent solubilization and reconstitution conditions, and the structural state of proteoliposomes by electron microscopy. We found that gamma-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 gamma-secretase can be restored to near native levels when properly reconstituted into a lipid bilayer environment. (C) 2010 Elsevier Inc. All rights reserved.