Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-387
Authors: Reinhardt, Sven
Stoye, Nicolai
Luderer, Mathias
Kiefer, Falk
Schmitt, Ulrich
Lieb, Klaus
Endres, Kristina
Title: Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks
Online publication date: 31-Jul-2018
Language: english
Abstract: ADAM10 is a metalloproteinase acting on the amyloid precursor protein (APP) as an alpha-secretase in neurons. Its enzymatic activity results in secretion of a neuroprotective APP cleavage product (sAPPalpha) and prevents formation of the amyloidogenic A-beta peptides, major hallmarks of Alzheimer’s disease (AD). Elevated ADAM10 levels appeared to contribute to attenuation of A-beta-Plaque formation and learning and memory deficits in AD mouse models. Therefore, it has been assumed that ADAM10 might represent a valuable target in AD therapy. Here we screened a FDA-approved drug library and identified disulfiram as a novel ADAM10 gene expression enhancer. Disulfiram increased ADAM10 production as well as sAPP-alpha in SH-SY5Y human neuronal cells and additionally prevented A-beta aggregation in an in vitro assay in a dose-dependent fashion. In addition, acute disulfiram treatment of Alzheimer model mice induced ADAM10 expression in peripheral blood cells, reduced plaque-burden in the dentate gyrus and ameliorated behavioral deficits. Alcohol-dependent patients are subjected to disulfiram-treatment to discourage alcohol-consumption. In such patients, enhancement of ADAM10 by disulfiram-treatment was demonstrated in peripheral blood cells. Our data suggest that disulfiram could be repurposed as an ADAM10 enhancer and AD therapeutic. However, efficacy and safety has to be analyzed in Alzheimer patients in the future.
DDC: 610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
Place: Mainz
DOI: http://doi.org/10.25358/openscience-387
URN: urn:nbn:de:hebis:77-publ-583995
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
Information on rights of use: https://creativecommons.org/licenses/by/4.0/
Journal: Scientific reports
8
Pages or article number: Art. 1329
Publisher: Macmillan Publishers Limited, part of Springer Nature
Publisher place: London
Issue date: 2018
ISSN: 2045-2322
Publisher URL: http://dx.doi.org/10.1038/s41598-018-19577-7
Publisher DOI: 10.1038/s41598-018-19577-7
Appears in collections:JGU-Publikationen

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