Neprilysin activity and expression are controlled by nicastrin

We recently demonstrated that the presenilin-dependent γ-secretase complex regulates the expression and activity of neprilysin, one of the main enzymes that degrade the amyloid β-peptide (Aβ) which accumulates in Alzheimer's disease. Here, we examined the influence of endogenous nicastrin (NCT), a member of the γ-secretase complex, on neprilysin physiology. We show that nicastrin deficiency drastically lowers neprilysin expression, membrane-bound activity and mRNA levels, but it did not modulate the expression of two other putative Aβ-cleaving enzymes, endothelin-converting enzyme and insulin-degrading enzyme. Furthermore, we show that nicastrin restores neprilysin activity and expression in nicastrin-deficient, but not presenilin-deficient fibroblasts, indicating that the control of neprilysin necessitates the complete γ-secretase complex harbouring its four reported components. Finally, we show that NCT expression peaked 24 h after NCT cDNA transfection of wild-type and NCT-/- fibroblasts, while neprilysin expression drastically increased only after 36 h and was maximal at 48 h. This delayed effect on neprilysin expression correlates well with our demonstration of an indirect γ-secretase-dependent modulation of neprilysin at its transcriptional level.