Mutations in the presenilin genes PS1 and PS2 are a major cause of early onset familial Alzheimer's disease (AD). Previous studies have suggested that presenilins have several functions, including gamma-secretase activity. It was also shown that presenilin expression is increased in the brains of some AD patients and ischemic rodents. The present study examines the effect of increased presenilin expression on protein synthesis. We show here that overexpression of wild-type PS2 (PS2wt) or PS2 mutant containing the FAD mutation N141I (PS2mut) in various cell lines inhibits the synthesis of coexpressed reporter and endogenous proteins. Furthermore, endogenous PS2 seems to be needed for translation inhibition since PS2 null fibroblasts were translationally more active than PS2(+/+) fibroblasts under conditions known to inhibit translation. Overexpression of PS1 also appeared to cause inhibition of protein synthesis, but its effect was much weaker than that of PS2. Taken together, the results suggest that increased expression of PS2 and possibly also of PS1 inhibits translation and that presenilins may function as regulators of protein synthesis.