New protease inhibitors prevent gamma-secretase-mediated production of Abeta40/42 without affecting Notch cleavage.
We have designed new non-peptidic potential inhibitors of gamma-secretase and examined their ability to prevent production of amyloid-beta 40 (Abeta40) and Abeta42 by human cells expressing wild-type and Swedish-mutant beta-amyloid precursor protein (betaAPP). Here we identify three such agents that markedly reduce recovery of both Abeta40 and Abeta42 produced by both cell lines, and increase that of C99 and C83, the carboxy-terminal fragments of betaAPP that are derived from beta-and alpha-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 mDeltaEnotch-1 cleavage that leads to generation of the Notch intracellular domain (NICD). These represent the first non-peptidic inhibitors that are able to prevent gamma-secretase cleavage of betaAPP without affecting processing of mDeltaEnotch-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 betaAPP and Notch maturation, presenilins are probably involved in the control of maturation processes upstream of enzymes that cleave gamma-secretase and Notch.
Petit
A
A
Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, 660 route des Lucioles, 06560 Valbonne, France.
Bihel
F
F
Alvès da Costa
C
C
Pourquié
O
O
Checler
F
F
Kraus
J L
JL
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D010446:Peptide Fragments / Q000096:biosynthesis*; D010641:Phenotype; D011233:Precipitin Tests; D053766:Presenilin-2; D011480:Protease Inhibitors / Q000494:pharmacology*; D051880:Receptors, Notch; D014162:Transfection
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; D011480:Protease Inhibitors; D051880:Receptors, Notch; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human