Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer\u2019s disease hallmarks

Falk Kiefer,Klaus Lieb,Mathias Luderer,Nicolai Stoye,Sven Reinhardt,Ulrich Schmitt,Kristina Endres

doi:10.1038/s41598-018-19577-7

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 (sAPP-alpha) 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.

Highlights

Alzheimer’s disease is the most prevalent dementia in the aging population
A library of 640 FDA-approved drugs was tested for potential influence on ADAM10 and BACE-1 transcriptional activity in neuronal cells
The initial dilution was chosen to reach a final concentration of 2 μM for acitretin, which served as an internal ADAM10-inducing control21. 627 out of 640 tested substances were found to be applicable for further testing

Summary

Introduction

Alzheimer’s disease is the most prevalent dementia in the aging population. With up to 15 million cases worldwide it represents a disease with high impact on medicinal care burden and patient numbers are estimated to increase further in the following years (e.g.1). The use of disulfiram in this clinical indication facilitated measurements of ADAM10 expression within peripheral blood cells in humans before and after two weeks of treatment with the newly identified drug.

Results

Conclusion