Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease

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.

Are improper kinetic models hampering drug development?

“…One drug candidate DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) has been described as having complex kinetic interactions with -secretase, in that at low amyloid precursor protein concentrations, low concentrations of DAPT have been observed to produce activation of -secretase catalytic activity but as DAPT concentrations are increased this turns into inhibition (Svedruzic, Popovic & Sendula-Jengic 2013). At higher concentrations of amyloid precursor protein DAPT only appears to inhibit the enzyme.…”

Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease

“…Interestingly, only about 6% of all of the Alzheimer's disease publications, or about 5876 entries, could be retrieved with a search focused on "Alzheimer AND gammasecretase OR beta-secretase". These numbers indicate that a wide range of possible pathogenic processes have been explored, and the main problem could be lack of insights at the key drug-target enzymes (Svedruzic et al, 2012(Svedruzic et al, , 2013Sambamurti et al, 2011;Shen and Kelleher, 2007). Without adequate insights in the catalytic mechanism of γ-secretase, development of the new drug candidates and the early diagnostic methods will remain an expensive guess-work with a high risk of failure (Doody et al, 2013;Tong et al, 2012;Svedruzic et al, 2013).…”

“…These numbers indicate that a wide range of possible pathogenic processes have been explored, and the main problem could be lack of insights at the key drug-target enzymes (Svedruzic et al, 2012(Svedruzic et al, , 2013Sambamurti et al, 2011;Shen and Kelleher, 2007). Without adequate insights in the catalytic mechanism of γ-secretase, development of the new drug candidates and the early diagnostic methods will remain an expensive guess-work with a high risk of failure (Doody et al, 2013;Tong et al, 2012;Svedruzic et al, 2013). Molecular and Cellular Neuroscience 67 (2015) [55][56][57][58][59][60][61][62][63][64][65] FAD mutations (Familial Alzheimer's disease), offer unique opportunities for analysis of pathogenic changes in γ-secretase activity and Aβ production (Chavez-Gutierrez et al, 2012;Pera et al, 2013;Potter et al, 2013;Shen and Kelleher, 2007;Svedruzic et al, 2012;Jonsson et al, 2012;Seidner et al, 2006;Kumar-Singh et al, 2006;Citron et al, 1992).…”

The Impact of Mathematical Modeling in Understanding the Mechanisms Underlying Neurodegeneration: Evolving Dimensions and Future Directions

“…Several studies have investigated the dynamics of the different amyloid species under the effect of γ‐secretase modulators 13, 60, 61, 62.Sortilin‐related proteins (SORLA) inhibit APP breakdown by interacting with them and limiting amyloidogenic proteolysis. SORLA dynamics have been modelled in AD 63, 64, 65.…”

“…Several studies have investigated the dynamics of the different amyloid species under the effect of γ‐secretase modulators 13, 60, 61, 62.…”