Gamma-secretase mediates the final proteolytic cleavage, which liberates amyloid 
beta-peptide (Abeta), the major component of senile plaques in the brains of 
Alzheimer disease patients. Therefore, gamma-secretase is a prime target for 
Abeta-lowering therapeutic strategies. gamma-Secretase is a protein complex 
composed of four different subunits, presenilin (PS), APH-1, nicastrin, and 
PEN-2, which are most likely present in a 1:1:1:1 stoichiometry. PS harbors the 
catalytically active site, which is critically required for the aspartyl 
protease activity of gamma-secretase. Moreover, numerous familial Alzheimer 
disease-associated mutations within the PSs increase the production of the 
aggregation-prone and neurotoxic 42-amino acid Abeta. Nicastrin may serve as a 
substrate receptor, although this has recently been challenged. PEN-2 is 
required to stabilize PS within the gamma-secretase complex. No particular 
function has so far been assigned to APH-1. The four components are sufficient 
and required for gamma-secretase activity. At least six different 
gamma-secretase complexes exist that are composed of different variants of PS 
and APH-1. All gamma-secretase complexes can exert pathological Abeta 
production. Assembly of the gamma-secretase complex occurs within the 
endoplasmic reticulum, and only fully assembled and functional gamma-secretase 
complexes are transported to the plasma membrane. Structural analysis by 
electron microscopy and chemical cross-linking reveals a water-containing 
cavity, which allows intramembrane proteolysis. Specific and highly sensitive 
gamma-secretase inhibitors have been developed; however, they interfere with the 
physiological function of gamma-secretase in Notch signaling and thus cause 
rather significant side effects in human trials. Modulators of gamma-secretase, 
which selectively affect the production of the pathological 42-amino acid Abeta, 
do not inhibit Notch signaling.