gamma-Secretase is a membrane-embedded multi-protein complex that catalyzes the 
final cut of the Alzheimer's disease-related amyloid precursor protein (APP) to 
amyloid-beta peptides of variable length (37-43 amino acids) via an unusual 
intramembrane cleavage. Recent findings propose that some commonly used 
non-steroidal anti-inflammatory drugs (NSAIDs) have the ability to modulate 
specifically gamma-secretase activity without inhibiting the enzyme as a whole. 
These drugs may shift the processing of APP from the longer amyloid-beta 42 
peptide towards shorter, less fibrillogenic and less toxic amyloid-beta species. 
We hypothesize that gamma-secretase activity, as an enzyme that is strictly 
associated with cellular membranes, is sensitive to alterations of the 
hydrophobic membrane environment. Here, we show that the gamma-secretase 
modulator and amyloid-beta 42-lowering drug sulindac sulfide alters the physical 
state of the membrane and strongly decreases fluidity of cellular membranes. 
Furthermore, sulindac sulfide changed the protein composition of membrane 
microdomains, the so-called lipid rafts. Most significantly, APP C-terminal 
fragments (CTFs) were redistributed from rafts towards non-raft membrane 
domains. This could be demonstrated also in cell-free assays, where in addition 
presenilin-1, the catalytic subunit of the gamma-secretase complex, was shifted 
out of lipid rafts. Together, these findings suggest that sulindac sulfide 
directly alters the membrane architecture and shifts the 
gamma-secretase-mediated cleavage of APP towards a hydrophobic environment where 
the enzyme-substrate complex is in a conformation for processing preferentially 
shorter amyloid-beta peptides.