Aβpp secretases are co-expressed with Aβpp in the pancreatic islets

Amyloid beta protein precursor is cleaved by beta- and gamma-secretases to produce A beta 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.-secretase. Each protein has a close homologue (BACE2 and PS2, respectively), whose roles in A beta PP 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 A beta PP, BACE, BACE2, PS1, and PS2 in the human pancreas. The insulin-producing beta cells were found to express A beta PP, 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 A beta PP 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.