Dataset Information

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

ABSTRACT:

Background

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

Results

A? 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of ?-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in ?-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 ?-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, ?-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 ?-secretase cannot lead to effective therapies, the pharmacodynamics of A?-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 ?-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of ?-secretase and the pathogenic changes in A? metabolism.

SUBMITTER: Svedruzic ZM

PROVIDER: S-EPMC3538728 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

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

Svedružić Željko M ŽM Popović Katarina K Šendula-Jengić Vesna V

PloS one 20130107 1

<h4>Background</h4>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.<h4>Results</h4>Aβ 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-r ...[more]

PMID: 23308095

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Project description:?-Secretase is an aspartyl intramembranal protease composed of presenilin, Nicastrin, Aph1, and Pen2 with 19 transmembrane domains. ?-Secretase cleaves the amyloid precursor proteins (APP) to release A? peptides that likely play a causative role in the pathogenesis of Alzheimer's disease (AD). In addition, ?-secretase cleaves Notch and other type I membrane proteins. ?-Secretase inhibitors (GSIs) have been developed and used for clinical studies. However, clinical trials have shown adverse effects of GSIs that are potentially linked with nondiscriminatory inhibition of Notch signaling, overall APP processing, and other substrate cleavages. Therefore, these findings call for the development of disease-modifying agents that target ?-secretase activity to lower levels of A?42 production without blocking the overall processing of ?-secretase substrates. ?-Secretase modulators (GSMs) originally derived from nonsteroidal anti-inflammatory drugs (NSAIDs) display such characteristics and are the focus of this review. However, first-generation GSMs have limited potential because of the low potency and undesired neuropharmacokinetic properties. This generation of GSMs has been suggested to interact with the APP substrate, ?-secretase, or both. To improve the potency and brain availability, second-generation GSMs, including NSAID-derived carboxylic acid and non-NSAID-derived heterocyclic chemotypes, as well as natural product-derived GSMs have been developed. Animal studies of this generation of GSMs have shown encouraging preclinical profiles. Moreover, using potent GSM photoaffinity probes, multiple studies unambiguously have showed that both carboxylic acid and heterocyclic GSMs specifically target presenilin, the catalytic subunit of ?-secretase. In addition, two types of GSMs have distinct binding sites within the ?-secretase complex and exhibit different A? profiles. GSMs induce a conformational change of ?-secretase to achieve modulation. Various models are proposed and discussed. Despite the progress of GSM research, many outstanding issues remain to be investigated to achieve the ultimate goal of developing GSMs as effective AD therapies.