Marambaud P, Chevallier N, Barelli H, Wilk S, Checler F
IPMC du CNRS, UPR411, Valbonne, France.
J Neurochem. 1997 Feb;68(2):698-703. doi: 10.1046/j.1471-4159.1997.68020698.x.
A major histopathological hallmark in Alzheimer's disease consists of the extracellular deposition of the amyloid beta-peptide (A beta) that is proteolytically derived from the beta-amyloid precursor protein (beta APP). An alternative, nonamyloidogenic cleavage, elicited by a protease called alpha-secretase, occurs inside the A beta sequence and gives rise to APP alpha, a major secreted C-terminal-truncated form of beta APP. 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 APP alpha secretion by these cells. Furthermore, we establish that a specific proteasome blocker, lactacystin, also induces increased secretion of A beta peptide in stably transfected HK293 cells overexpressing wild-type beta APP751. Altogether, this study represents the first identification of a proteolytic activity, namely, the proteasome, contributing likely through yet unknown intracellular relays, to the alpha-secretase pathway in human cells.
阿尔茨海默病的一个主要组织病理学特征是淀粉样β肽（Aβ）在细胞外沉积，该肽是由β淀粉样前体蛋白（βAPP）经蛋白水解产生的。一种由名为α-分泌酶的蛋白酶引发的非淀粉样生成性切割，发生在Aβ序列内部，并产生APPα，这是βAPP的一种主要分泌型C末端截短形式。在此，我们证明人胚肾293（HK293）细胞含有一种可归因于蛋白酶体的类胰凝乳蛋白酶活性，并且该酶的选择性抑制剂可降低这些细胞中佛波醇12,13-二丁酸酯敏感的APPα分泌。此外，我们证实一种特异性蛋白酶体阻断剂乳胞素，也会在稳定转染了过表达野生型βAPP751的HK293细胞中诱导Aβ肽分泌增加。总之，本研究首次鉴定出一种蛋白水解活性，即蛋白酶体，它可能通过尚未明确的细胞内信号传导途径，对人类细胞中的α-分泌酶途径产生影响。
