In this review, we discuss the biology of gamma-secretase, an enigmatic enzyme 
complex that is responsible for the generation of the amyloid-beta peptide that 
constitutes the amyloid plaques of Alzheimer's disease. We begin with a brief 
review on the processing of the amyloid precursor protein and a brief discussion 
on the family of enzymes involved in regulated intramembrane proteolysis, of 
which gamma-secretase is a member. We then identify the four major components of 
the gamma-secretase complex - presenilin, nicastrin, Aph-1, and Pen-2 - with a 
focus on the identification of each and the role that each plays in the 
maturation and activity of the complex. We also discuss two new proteins that 
may play a role in modulating the assembly and activity of the gamma-secretase 
complex. Next, we summarize the known subcellular locations of each 
gamma-secretase component and the sites of gamma-secretase activity, as defined 
by the production of Abeta. Finally, we close by synthesizing all of the 
included topics into an overarching model for the assembly and trafficking of 
the gamma-secretase complex, which serves as a launching point for further 
questions into the biology and function of gamma-secretase in Alzheimer's 
disease.