Genetic and biological studies provide evidence that the production and 
deposition of amyloid-beta peptides (Abeta) contribute to the etiology of 
Alzheimer's disease. beta- and gamma-secretases, which are responsible for the 
generation of Abeta, are plausible molecular targets for Alzheimer's disease 
treatment. gamma-Secretase is an unusual aspartic protease that cleaves the 
scissile bond within the transmembrane domain. This unusual enzyme is composed 
of a high molecular weight membrane protein complex containing presenilin, 
nicastrin, Aph-1 and Pen-2. Drugs that regulate the production of Abeta by 
inhibiting or modulating gamma-secretase activity could provide a 
disease-modifying effect on Alzheimer's disease, although recent studies suggest 
that gamma-secretase plays important roles in cellular signaling including 
Notch. Thus, understanding the molecular mechanism whereby gamma-secretase 
recognizes and cleaves its substrate is a critical issue for the development of 
compounds that specifically regulate Abeta-generating gamma-secretase activity. 
This review focuses on the structure and function relationship of 
gamma-secretase complex and the mode of action of the gamma-secretase 
inhibitors.