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New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage

Abstract

We have designed new non-peptidic potential inhibitors of γ-secretase and examined their ability to prevent production of amyloid-β 40 (Aβ40) and Aβ42 by human cells expressing wild-type and Swedish-mutant β-amyloid precursor protein (βAPP). Here we identify three such agents that markedly reduce recovery of both Aβ40 and Aβ42 produced by both cell lines, and increase that of C99 and C83, the carboxy-terminal fragments of βAPP that are derived from β-and α-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 mΔEnotch-1 cleavage that leads to generation of the Notch intracellular domain (NICD). These represent the first non-peptidic inhibitors that are able to prevent γ-secretase cleavage of βAPP without affecting processing of mΔEnotch-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 βAPP and Notch maturation, presenilins are probably involved in the control of maturation processes upstream of enzymes that cleave γ-secretase and Notch.

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Figure 1: Synthesis of JLK inhibitors.
Figure 2: Effect of JLK inhibitors on βAPP maturation in HEK293 cells expressing wild-type or Swedish-mutant βAPP.
Figure 3: Effect of JLK inhibitors on Aβ40 and Aβ42 generation in HEK293 cells expressing wild-type and Swedish-mutant βAPP.
Figure 4: Effect of JLK inhibitors and DFK167 on endoproteolysis of endogenous or overexpressed presenilins.
Figure 5: Effect of JLK inhibitors and DFK167 on NICD generation by HEK293 cells overexpressing Myc-tagged mΔENotch.

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Acknowledgements

We thank M. Delaage and C. Henderson for JLK inhibitors, R. Kopan for mΔENotch-1 and NICD constructs, and the following for antibodies: T. Hartmann and K. Beyreuther for WO2, M. Goedert for BR188, L. Pradier for 9E10, M. Savage for 207, D. Schenk for 10D5C, and T. Tabira and W. Araki for Ab111, Ab333 and Ab444.

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Correspondence to Frédéric Checler or Jean-Louis Kraus.

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Petit, A., Bihel, F., da Costa, C. et al. New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage. Nat Cell Biol 3, 507–511 (2001). https://doi.org/10.1038/35074581

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