The What, Where, and How of γ-Secretase Complex Assembly

Here we discuss the biology of γ-secretase, an enigmatic enzyme complex that is responsible for the generation of the β-amyloid 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 γ-secretase is a member. We then identify the four major components of the γ-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. Next, we summarize the known subcellular locations of each γ-secretase component and the sites of γ-secretase activity, as defined by the production of β-amyloid. Finally, we close by synthesizing all of the included topics into an overarching model for the assembly and trafficking of the γ-secretase complex, which serves as a launching point for further questions into the biology and function of γ-secretase in Alzheimer’s disease.