Résumé
: A major histopathological hallmark in Alzheimer's disease consists of the extracellular deposition of the amyloid β‐peptide (Aβ) that is proteolytically derived from the β‐amyloid precursor protein (βAPP). An alternative, nonamyloidogenic cleavage, elicited by a protease called α‐secretase, occurs inside the Aβ sequence and gives rise to APPα, a major secreted C‐terminal‐truncated form of βAPP. Here, we demonstrate that human embryonic kidney 293 (HK293) cells contain a chymotryptic‐like activity that can be ascribed to the proteasome and that selective inhibitors of this enzyme reduce the phorbol 12,13‐dibutyrate‐sensitive APPα secretion by these cells. Furthermore, we establish that a specific proteasome blocker, lactacystin, also induces increased secretion of Aβ peptide in stably transfected HK293 cells overexpressing wild‐type βAPP751. Altogether, this study represents the first identification of a proteolytic activity, namely, the proteasome, contributing likely through yet unknown intracellular relays, to the α‐secretase pathway in human cells.