Abstract
BackgroundSelective 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.ResultsAβ 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.SignificancePresented 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.
Highlights
Alzheimer’s disease is a slowly progressing neurodegenerative disorder with a fatal outcome [1,2]
Similar to the previous studies [9,14], we find that DAPT exhibits a biphasic ‘‘activation-inhibition’’ dose-response curves
Six free fit parameters can be resolved by nonlinear regression: initial activity (IA), calculated maximal activity plateau (MA), maximal inhibition (MI), EC50 for activation, IC50 for inhibition, and the corresponding Hill’s coefficients (Table 1)
Summary
Alzheimer’s disease is a slowly progressing neurodegenerative disorder with a fatal outcome [1,2]. Large efforts in basic and pharmaceutical research are steadily providing diverse therapeutic strategies and potential targets [1,3,4,5]. Some of the therapeutic approaches have reached clinical trials, including the phase III [1]. None of the clinical trials have led to effective therapies due to lack of desired effects or due to unacceptable toxic side-effects [1]. The repetitive failures of diverse therapeutic approaches show that we still lack some key insights into molecular mechanism behind this complex disease. Selective modulation of different Ab products of an intramembrane protease c-secretase, could be the most promising strategy for development of effective therapies for Alzheimer’s disease. We describe how different drugcandidates can modulate c-secretase activity in cells, by studying how DAPT affects changes in c-secretase activity caused by gradual increase in Ab metabolism
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