Journal of Biological Chemistry
Volume 276, Issue 48, 30 November 2001, Pages 45394-45402
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MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY
Pharmacological Knock-down of the Presenilin 1 Heterodimer by a Novel γ-Secretase Inhibitor: IMPLICATIONS FOR PRESENILIN BIOLOGY*

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Intramembranous cleavage of the β-amyloid precursor protein by γ-secretase is the final processing event generating amyloid-β peptides, which are thought to be causative agents for Alzheimer's disease. Missense mutations in the presenilin genes co-segregate with early-onset Alzheimer's disease, and, recently, a close biochemical linkage between presenilins and the identity of γ-secretase has been established. Here we describe for the first time that certain potent γ-secretase inhibitors are able to interfere with the endoproteolytic processing of presenilin 1 (PS1). In addition, we identified a novel γ-secretase inhibitor, {1S-benzyl-4R-[1-(5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R,S)-ylcarbamoyl)-S-ethylcarbamoyl]-2R-hydroxy-5-phenyl-pentyl}-carbamic acid tert-butyl ester (CBAP), which not only physically interacts with PS1, but upon chronic treatment produces a “pharmacological knock-down” of PS1 fragments. This indicates that the observed accumulation of full-length PS1 is caused by a direct inhibition of its endoproteolysis. The subsequent use of CBAP as a biological tool to increase full-length PS1 levels in the absence of exogenous PS1 expression has provided evidence that wild-type PS1 endoproteolysis is not required either for PS1/γ-secretase complex assembly or trafficking. Furthermore, in cell-based systems CBAP does not completely recapitulate PS1 loss-of-function phenotypes. Even though the β-amyloid precursor protein cleavage and the S3 cleavage of the Notch receptor are inhibited by CBAP, an impairment of Trk receptor maturation was not observed.

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Published, JBC Papers in Press, September 26, 2001, DOI 10.1074/jbc.M103075200

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