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PLoS One. 2013;8(1):e50759. doi: 10.1371/journal.pone.0050759. Epub 2013 Jan 7.

Modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer's disease.

Author information

1
Medical Biochemistry, PB Rab, Faculty of Medicine, University of Rijeka, Rab, Croatia. zsvedruz@biol.pmf.hr

Erratum in

  • PLoS One. 2013;8(9). doi:10.1371/annotation/7cf2c08a-44d2-4db8-8584-d2e62e18d05d.

Abstract

BACKGROUND:

Selective modulation of different Aβ products of an intramembrane protease γ-secretase, could be the most promising strategy for development of effective therapies for Alzheimer's disease. We describe how different drug-candidates can modulate γ-secretase activity in cells, by studying how DAPT affects changes in γ-secretase activity caused by gradual increase in Aβ metabolism.

RESULTS:

Aβ 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of γ-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in γ-secretase's kinetic affinity for its substrate, which can make the enzyme increasingly more saturated with otherwise sub-saturating substrate. The noncompetitive inhibition that prevails at the saturating substrate can decrease the maximal activity. The synergistic activation-inhibition effects can drastically reduce γ-secretase's capacity to process its physiological substrates. This reduction makes the biphasic inhibitors exceptionally prone to the toxic side-effects and potentially pathogenic. Without the modulation, γ-secretase activity on it physiological substrate in cells is only 14% of its maximal activity, and far below the saturation.

SIGNIFICANCE:

Presented mechanism can explain why moderate inhibition of γ-secretase cannot lead to effective therapies, the pharmacodynamics of Aβ-rebound phenomenon, and recent failures of the major drug-candidates such as semagacestat. Novel improved drug-candidates can be prepared from competitive inhibitors that can bind to different sites on γ-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of γ-secretase and the pathogenic changes in Aβ metabolism.

PMID:
23308095
PMCID:
PMC3538728
DOI:
10.1371/journal.pone.0050759
[Indexed for MEDLINE]
Free PMC Article
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