Pharmacological knock-down of the presenilin 1 heterodimer by a novel γ-secretase inhibitor: implications for presenilin biology

Abstract:

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 …

Año de publicación:

2001

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Fuente:

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