Proteasome contributes to the α-secretase pathway of amyloid precursor protein in human cells

Philippe Marambaud, Nathalie Chevallier, Helene Barelli, Sherwin Wilk, Frederic Checler

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44 Scopus citations


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.

Original languageEnglish
Pages (from-to)698-703
Number of pages6
JournalJournal of Neurochemistry
Issue number2
StatePublished - Feb 1997


  • Alzheimer's disease
  • Amyloid β-peptide
  • Human kidney 293 cells
  • Proteasome
  • α-Secretase
  • β-Amyloid precursor protein


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