Abstract
The human amyloid precursor protein (APP) is processed by the nonamyloidogenic and the amyloidogenic catabolic pathways. The sequential cleavage of APP by the β‐ and γ‐secretase activities, known as the amyloidogenic processing of APP, leads to the formation of the amyloid‐β peptide (Aβ). Aβ is the main constituent of the amyloid core of senile plaques, a typical hallmark of Alzheimer's disease. In addition to secretases, other cellular proteolytic activities, like the proteasome, might participate in the metabolism of APP. We investigated the consequence of proteasome inhibition on the amyloidogenic processing of human APP. CHO cells and primary cultures of rat cortical neurons expressing human APP or a protein corresponding to its β‐cleaved C‐terminal fragment (C99) were treated with lactacystin, an irreversible inhibitor of the chymotrypsin‐like activity of the proteasome. Lactacystin significantly decreased the level of Aβ produced from APP in both cellular models, whereas the production of Aβ from C99 was not affected. Lactacystin did not inhibit γ‐secretase activity but was found to inhibit the β‐cleavage of APP, leading to a proportional decrease in Aβ production. Although lactacystin did not inhibit the catalytic activity of recombinant BACE1, a decrease in neuronal β‐secretase activity was measured after treatment with lactacystin. © 2006 Wiley‐Liss, Inc.