The role of presenilin-1 in the γ-secretase cleavage of the amyloid precursor protein of Alzheimer's disease

Presenilin-1 (PS1) is required for the release of the intracellular domain of Notch from the plasma membrane as well as for the cleavage of the amyloid precursor protein (APP) at the gamma-secretase cleavage site. It remains to be demonstrated whether PS1 acts by facilitating the activity of the protease concerned or is the protease itself. PS1 could have a gamma-secretase activity by itself or could traffic APP and Notch to the appropriate cellular compartment for processing. Human APP 695 and PS1 were coexpressed in Sf9 insect cells, in which endogenous gamma-secretase activity is not detected. In baculovirus-infected Sf9 cells, PS1 undergoes endoproteolysis and interacts with APP. However, PSI does not cleave APP in Sf9 cells. In CHO cells, endocytosis of APP is required for A beta secretion. Deletion of the cytoplasmic sequence of APP (APP Delta C) inhibits both APP endocytosis and A beta production. When APP Delta C and PS1 are coexpressed in CHO cells, A beta is secreted without endocytosis of APP. Taken together, these results conclusively show that, although PS1 does not cleave APP in Sf9 cells, PS1 allows the secretion of A beta without endocytosis of APP by CHO cells.