Effects of Specific Protease Inhibitors on Amyloid β-Protein 42 Secretion

Abstract

Amyloid β-protein (Aβ) is classified into two subspecies defined by its C-terminal length, designated Aβ40 and Aβ42. Although Aβ42 accounts for only ∼10% of secreted Aβ, this particular species is the most dominant species in Aβ deposits in Alzheimer’s disease (AD) and normal aged brains and appears to be the initially deposited species. Secretion levels of Aβ42 have been shown to increase in patients affected by any form of early-onset familial AD. Thus, the suppression of Aβ42 production or secretion could be a therapeutic strategy for AD. In this study, we examined whether protease inhibition affects the Aβ42 secretion ratio (Aβ42: total Aβ). Using specific inhibitors, we determined that the inhibition of calpain but not proteasome induces an increased Aβ42 secretion in cultured cells. These data suggest that calpain differentially affects the γ-secretases generating Aβ40 and Aβ42 and indicate the possibility of developing compounds that reduce Aβ42 production and secretion though this pathway.