P. Marambaud et al., PROTEASOME CONTRIBUTES TO THE ALPHA-SECRETASE PATHWAY OF AMYLOID PRECURSOR PROTEIN IN HUMAN-CELLS, Journal of neurochemistry, 68(2), 1997, pp. 698-703
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 (b
eta APP). An alternative, nonamyloidogenic cleavage, elicited by a pro
tease called alpha-secretase, occurs inside the A beta sequence and gi
ves rise to APP alpha, a major secreted C-terminal-truncated form of b
eta 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 ph
orbol 12,13-dibutyrate-sensitive APP alpha secretion by these cells. F
urthermore, we establish that a specific proteasome blocker, lactacyst
in, also induces increased secretion of A beta peptide in stably trans
fected HK293 cells overexpressing wild-type beta APP751. Altogether, t
his study represents the first identification of a proteolytic activit
y, namely, the proteasome, contributing likely through yet unknown int
racellular relays, to the alpha-secretase pathway in human cells.