Effects of specific protease inhibitors on amyloid beta-protein 42 secretion.

Amyloid beta-protein (Abeta) is classified into two subspecies defined by its C-terminal length, designated Abeta40 and Abeta42. Although Abeta42 accounts for only approximately 10% of secreted Abeta, this particular species is the most dominant species in Abeta deposits in Alzheimer's disease (AD) and normal aged brains and appears to be the initially deposited species. Secretion levels of Abeta42 have been shown to increase in patients affected by any form of early-onset familial AD. Thus, the suppression of Abeta42 production or secretion could be a therapeutic strategy for AD. In this study, we examined whether protease inhibition affects the Abeta42 secretion ratio (Abeta42: total Abeta). Using specific inhibitors, we determined that the inhibition of calpain but not proteasome induces an increased Abeta42 secretion in cultured cells. These data suggest that calpain differentially affects the gamma-secretases generating Abeta40 and Abeta42 and indicate the possibility of developing compounds that reduce Abeta42 production and secretion though this pathway.