Cargando…

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

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 study...

Descripción completa

Detalles Bibliográficos
Autores principales: Svedružić, Željko M., Popović, Katarina, Šendula-Jengić, Vesna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538728/
https://www.ncbi.nlm.nih.gov/pubmed/23308095
http://dx.doi.org/10.1371/journal.pone.0050759
_version_ 1782255003512078336
author Svedružić, Željko M.
Popović, Katarina
Šendula-Jengić, Vesna
author_facet Svedružić, Željko M.
Popović, Katarina
Šendula-Jengić, Vesna
author_sort Svedružić, Željko M.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3538728
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-35387282013-01-10 Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease Svedružić, Željko M. Popović, Katarina Šendula-Jengić, Vesna PLoS One Research Article 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. Public Library of Science 2013-01-07 /pmc/articles/PMC3538728/ /pubmed/23308095 http://dx.doi.org/10.1371/journal.pone.0050759 Text en © 2013 Svedružić et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Svedružić, Željko M.
Popović, Katarina
Šendula-Jengić, Vesna
Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease
title Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease
title_full Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease
title_fullStr Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease
title_full_unstemmed Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease
title_short Modulators of γ-Secretase Activity Can Facilitate the Toxic Side-Effects and Pathogenesis of Alzheimer's Disease
title_sort modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of alzheimer's disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538728/
https://www.ncbi.nlm.nih.gov/pubmed/23308095
http://dx.doi.org/10.1371/journal.pone.0050759
work_keys_str_mv AT svedruziczeljkom modulatorsofgsecretaseactivitycanfacilitatethetoxicsideeffectsandpathogenesisofalzheimersdisease
AT popovickatarina modulatorsofgsecretaseactivitycanfacilitatethetoxicsideeffectsandpathogenesisofalzheimersdisease
AT sendulajengicvesna modulatorsofgsecretaseactivitycanfacilitatethetoxicsideeffectsandpathogenesisofalzheimersdisease