Presenilin 1 and Presenilin 2 Target γ-Secretase Complexes to Distinct Cellular Compartments

γ-Secretase complexes achieve the production of amyloid peptides playing a key role in Alzheimer disease. These proteases have many substrates involved in important physiological functions. They are composed of two constant subunits, nicastrin and PEN2, and two variable ones, presenilin (PS1 or PS2) and APH1 (APH1aL, APH1aS, or APH1b). Whether the composition of a given γ-secretase complex determines a specific cellular targeting remains unsolved. Here we combined a bidirectional inducible promoter and 2A peptide technology to generate constructs for the temporary, stoichiometric co-expression of six different combinations of the four γ-secretase subunits including EGFP-tagged nicastrin. These plasmids allow for the formation of functional γ-secretase complexes displaying specific activities and maturations. We show that PS1-containing γ-secretase complexes were targeted to the plasma membrane, whereas PS2-containing ones were addressed to the trans-Golgi network, to recycling endosomes, and, depending on the APH1-variant, to late endocytic compartments. Overall, these novel constructs unravel a presenilin-dependent subcellular targeting of γ-secretase complexes. These tools should prove useful to determine whether the cellular distribution of γ-secretase complexes contributes to substrate selectivity and to delineate regulations of their trafficking.