Nature Cell Biology
3, 507 - 511 (2001)
Published online: 12 April 2001; | doi:10.1038/35074581
New protease inhibitors prevent  -secretase-mediated production of A 40/42 without affecting Notch cleavageAgnès Petit1, 4, Frédéric Bihel4, 2, Cristine Alvès da Costa1, Olivier Pourquié3, Frédéric Checler1, 4
& Jean-Louis Kraus4, 21
Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, 660 route des Lucioles, 06560 Valbonne, France
2
Laboratoire de Chimie Biomoléculaire, Faculté des Sciences de Luminy, Université de la Méditerranée, Marseille, France
3
LGPD Unité Mixte de Recherche 6545, Marseille, France
4
These authors contributed equally to this work
Correspondence should be addressed to Frédéric Checler checler@ipmc.cnrs.fr or Jean-Louis Kraus kraus@luminy.univ-msr.frWe have designed new non-peptidic potential inhibitors of  -secretase and examined their ability to prevent production of amyloid- 40 (A40) and A42 by human cells expressing wild-type and Swedish-mutant -amyloid precursor protein (APP). Here we identify three such agents that markedly reduce recovery of both A40 and A42 produced by both cell lines, and increase that of C99 and C83, the carboxy-terminal fragments of APP that are derived from -and  -secretase, respectively. Furthermore, we show that these inhibitors do not affect endoproteolysis of endogenous or overexpressed presenilins. These inhibitors are totally unable to affect the m Enotch-1 cleavage that leads to generation of the Notch intracellular domain (NICD). These represent the first non-peptidic inhibitors that are able to prevent -secretase cleavage of APP without affecting processing of mEnotch-1 or endoproteolysis of presenilins. The distinction between these two proteolytic events, which are both prevented by disruption of presenilin genes, indicates that although they are intimately linked with APP and Notch maturation, presenilins are probably involved in the control of maturation processes upstream of enzymes that cleave -secretase and Notch.
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