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

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.

Impact of Acute and Chronic Amyloid-β Peptide Exposure on Gut Microbial Commensals in the Mouse

“…were maintained by crossbreeding with C57BL/6J background as described in Reinhardt et al (2018). Animals aged 9-10 weeks were used and non-transgenic offspring served as control and for acute treatment with peptides.…”

Repurposing Disulfiram (Tetraethylthiuram Disulfide) as a Potential Drug Candidate against Borrelia burgdorferi In Vitro and In Vivo

“…Below their respective CACs, these drugs exist in a classic monomeric form where, at sufficiently high (monomeric) concentrations, they are toxic to cells; in contrast, above their CACs, these drugs form colloidal aggregates that are substantially less cytotoxic in cell assays [ 37 , 38 ]. In addition, it has been reported that disulfiram producing a biphasic cytotoxic response in some breast cancer cell lines [ 39 ], human tumor cell lines [ 40 ], and neuronal cells [ 41 ]. In these cell lines 1 μM disulfiram was toxic involving consistent loss of cell viability.…”

Disulfiram (Tetraethylthiuram Disulfide) in the Treatment of Lyme Disease and Babesiosis: Report of Experience in Three Cases

“…Disulfiram has been recognized to have a novel unanticipated utility for addictions other than alcohol [85], as an anti-cancer agent [105], and it reduced plaque-burden in a mouse model of Alzheimer’s disease [106].…”