Amyloid beta protein precursor is cleaved by beta- and gamma-secretases to produce Abeta peptides which deposit in amyloid plaques in Alzheimer's disease (AD) brain. A recently identified beta-site cleaving enzyme (BACE) appears to fulfill the requirements for beta-secretase, and presenilin-1 (PS1) appears to constitute the catalytic component of gamma-secretase. Each protein has a close homologue (BACE2 and PS2, respectively), whose roles in AbetaPP cleavage remain uncertain. All four of these genes have been reported to be expressed in the human pancreas, but the cell types expressing these genes remains unknown. We demonstrate here the cell-specific expression of AbetaPP, BACE, BACE2, PS1, and PS2 in the human pancreas. The insulin-producing betacells were found to express AbetaPP, BACE and PS2 at high levels, and PS1 at a lower level. The other islet cell types expressed none of these five genes. By contrast, the exocrine ductal cells of the pancreas expressed AbetaPP and BACE2 selectively. These results suggest that secretase inhibitors under development for the treatment of AD, particularly those that target BACE, may have potential for adverse effects on pancreatic beta cell function, and therefore glycemic control.