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Cited by 58Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

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

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Reinhardt, Sven, Stoye, Nicolai, Luderer, Mathias, Kiefer, Falk, Schmitt, Ulrich, Lieb, Klaus, Endres, Kristina·2018·Scientific Reports
DOI 10.1038/s41598-018-19577-7PMC PMC5778060
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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.

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  1. [1]Wimo A The worldwide costs of dementia 2015 and comparisons with 2010 Alzheimers Dement 2017 13 1 7 10.1016/j.jalz.2016.07.150 27583652 PMC5232417 · DOI · Paper page
  2. [2]Dorszewska J Prendecki M Oczkowska A Dezor M Kozubski W Molecular Basis of Familial and Sporadic Alzheimer’s Disease Curr Alzheimer Res 2016 13 952 963 10.2174/1567205013666160314150501 26971934 · DOI
  3. [3]Hardy J The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the “amyloid cascade hypothesis” FEBS J 2017 284 1040 1044 10.1111/febs.14004 28054745 · DOI · Paper page
  4. [4]Bachurin, S. O., Bovina, E. V. & Ustyugov, A. A. Drugs in Clinical Trials for Alzheimer’s Disease: The Major Trends. Med Res Rev, 10.1002/med.21434 (2017). 28084618 · DOI
  5. [5]Milelli, A. et al. Tacrine-based Multifunctional Agents in Alzheimer’s Disease: an Old Story in Continuous Development. Curr Med Chem, 10.2174/0929867324666170309123920 (2017). 28294041 · DOI
  6. [6]Sang Z Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer’s disease Eur J Med Chem 2017 135 307 323 10.1016/j.ejmech.2017.04.054 28458136 · DOI
  7. [7]Unzeta M Multi-Target Directed Donepezil-Like Ligands for Alzheimer’s Disease Front Neurosci 2016 10 205 10.3389/fnins.2016.00205 27252617 PMC4879129 · DOI
  8. [8]Lammich S Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease Proc Natl Acad Sci USA 1999 96 3922 3927 10.1073/pnas.96.7.3922 10097139 PMC22396 · DOI
  9. [9]Vassar R Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999 286 735 741 10.1126/science.286.5440.735 10531052 · DOI · Paper page
  10. [10]Postina R A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model J Clin Invest 2004 113 1456 1464 10.1172/JCI20864 15146243 PMC406531 · DOI · Paper page
  11. [12]Jorissen E The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex J Neurosci 2010 30 4833 4844 10.1523/JNEUROSCI.5221-09.2010 20371803 PMC2921981 · DOI · Paper page
  12. [13]Bell KF Zheng L Fahrenholz F Cuello AC ADAM-10 over-expression increases cortical synaptogenesis Neurobiol Aging 2008 29 554 565 10.1016/j.neurobiolaging.2006.11.004 17187903 · DOI
  13. [14]Roberds SL BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics Hum Mol Genet 2001 10 1317 1324 10.1093/hmg/10.12.1317 11406613 · DOI · Paper page
  14. [16]Vassar R Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects J Neurochem 2014 130 4 28 10.1111/jnc.12715 24646365 PMC4086641 · DOI
  15. [17]Endres K Deller T Regulation of Alpha-Secretase ADAM10 In vitro andIn vivo: Genetic, Epigenetic, and Protein-Based Mechanisms Front Mol Neurosci. 2017 10 56 10.3389/fnmol.2017.00056 28367112 PMC5355436 · DOI
  16. [18]Alonso AD Beharry C Corbo CP Cohen LS Molecular mechanism of prion-like tau-induced neurodegeneration Alzheimers Dement 2016 12 1090 1097 10.1016/j.jalz.2015.12.014 27126544 · DOI · Paper page
  17. [19]Schuck F Extract of Caragana sinica as a potential therapeutic option for increasing alpha-secretase gene expression Phytomedicine 2015 22 1027 1036 10.1016/j.phymed.2015.08.001 26407945 · DOI
  18. [20]Meineck, M., Schuck, F., Abdelfatah, S., Efferth, T. a. & Endres, K.Identification of Phlogacantholide C as a Novel ADAM10 Enhancer from Traditional Chinese Medicinal Plants. Medicines3 (2016). PMC5456242 28930140
  19. [21]Tippmann F Hundt J Schneider A Endres K Fahrenholz F Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin FASEB J 2009 23 1643 1654 10.1096/fj.08-121392 19144697 · DOI
  20. [22]Yoon S Baik JH Dopamine D2 receptor-mediated epidermal growth factor receptor transactivation through a disintegrin and metalloprotease regulates dopaminergic neuron development via extracellular signal-related kinase activation J Biol Chem 2013 288 28435 28446 10.1074/jbc.M113.461202 23955337 PMC3789945 · DOI
  21. [23]Xie HR Hu LS Li GY SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson’s disease Chin Med J (Engl) 2010 123 1086 1092 20497720
  22. [24]Reagan-Shaw S Nihal M Ahmad N Dose translation from animal to human studies revisited FASEB J 2008 22 659 661 10.1096/fj.07-9574LSF 17942826 · DOI · Paper page
  23. [25]Hopfer SM Increased nickel concentrations in body fluids of patients with chronic alcoholism during disulfiram therapy Res Commun Chem Pathol Pharmacol 1987 55 101 109 3563101
  24. [26]Gessner, P. K. G. A. T. Disulfiram and its metabolite, Diethyldithiocarbamate. (Springer Science+Business Media, B.V. 1992).
  25. [27]Mezyk-Kopec R Identification of ADAM10 as a major TNF sheddase in ADAM17-deficient fibroblasts Cytokine 2009 46 309 315 10.1016/j.cyto.2009.03.002 19346138 · DOI
  26. [28]Hammond RS Tull LE Stackman RW On the delay-dependent involvement of the hippocampus in object recognition memory Neurobiol Learn Mem 2004 82 26 34 10.1016/j.nlm.2004.03.005 15183168 · DOI · Paper page
  27. [29]Deacon RM Croucher A Rawlins JN Hippocampal cytotoxic lesion effects on species-typical behaviours in mice Behav Brain Res 2002 132 203 213 10.1016/S0166-4328(01)00401-6 11997150 · DOI
  28. [30]Kim TW Drug repositioning approaches for the discovery of new therapeutics for Alzheimer’s disease Neurotherapeutics 2015 12 132 142 10.1007/s13311-014-0325-7 25549849 PMC4322062 · DOI
  29. [31]Kawahara K Oral administration of synthetic retinoid Am80 (Tamibarotene) decreases brain beta-amyloid peptides in APP23 mice Biol Pharm Bull 2009 32 1307 1309 10.1248/bpb.32.1307 19571405 · DOI
  30. [32]Kawahara K Cooperative therapeutic action of retinoic acid receptor and retinoid x receptor agonists in a mouse model of Alzheimer’s disease J Alzheimers Dis 2014 42 587 605 24916544
  31. [33]Dogra S Yadav S Acitretin in psoriasis: an evolving scenario Int J Dermatol 2014 53 525 538 10.1111/ijd.12365 24601982 · DOI
  32. [34]Endres K Increased CSF APPs-alpha levels in patients with Alzheimer disease treated with acitretin Neurology 2014 83 1930 1935 10.1212/WNL.0000000000001017 25344383 · DOI
  33. [35]Milosch N Holo-APP and G-protein-mediated signaling are required for sAPPalpha-induced activation of the Akt survival pathway Cell Death Dis 2014 5 e1391 10.1038/cddis.2014.352 25165877 PMC4454324 · DOI
  34. [36]Winefield RD N-acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in rat and human plasma after disulfiram administration J Pharm Biomed Anal 2015 107 518 525 10.1016/j.jpba.2015.01.036 25720821 PMC4410022 · DOI
  35. [37]Puglielli L Ellis BC Saunders AJ Kovacs DM Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis J Biol Chem 2003 278 19777 19783 10.1074/jbc.M300466200 12649271 · DOI
  36. [38]Gil-Bea F Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer’s disease brain EMBO Mol Med 2012 4 1097 1111 10.1002/emmm.201201462 22933306 PMC3491839 · DOI
  37. [39]Wilson A Disulfiram implantation in alcoholism treatment. A review J Stud Alcohol 1975 36 555 565 10.15288/jsa.1975.36.555 239278 · DOI
  38. [40]Lemere F Disulfiram as a sedative in alcoholism Q J Stud Alcohol 1953 14 197 199 13064374
  39. [41]Mohapatra S Rath NR Disulfiram Induced Psychosis Clin Psychopharmacol Neurosci 2017 15 68 69 10.9758/cpn.2017.15.1.68 28138114 PMC5290718 · DOI
  40. [42]de Melo RC Lopes R Alves JC A case of psychosis in disulfiram treatment for alcoholism Case Rep Psychiatry 2014 2014 561092 24818034 PMC4003787
  41. [43]Heath RG Nesselhof W Jr. Bishop MP Byers LW Behavioral and Metabolic Changes Associated with Administration of Tetraethylthiuram Disulfide (Antabuse) Dis Nerv Syst 1965 26 99 105 14256068
  42. [44]Payne RW Carpenter G Kessel N Effect of antabuse on intellectual functioning Dis Nerv Syst 1965 26 655 658 5831701
  43. [45]Prigatano GP Neuropsychological functioning of recidivist alcoholics treated with disulfiram: a follow-up report Int J Addict 1980 15 287 294 10.3109/10826088009040016 7399760 · DOI
  44. [46]Peeke SC Effect of disulfiram on cognition, subjective response, and cortical-event-related potentials in nonalcoholic subjects Alcohol Clin Exp Res 1979 3 223 229 10.1111/j.1530-0277.1979.tb05304.x 384831 · DOI
  45. [47]Savolainen K Hervonen H Lehto VP Mattila MJ Neurotoxic effects of disulfiram on autonomic nervous system in rat Acta Pharmacol Toxicol (Copenh) 1984 55 339 344 10.1111/j.1600-0773.1984.tb01992.x 6528806 · DOI
  46. [48]Molinengo L Oggero L Ghi P Orsetti M Action of a chronic disulfiram administration on memory decay and on central cholinergic and adrenergic systems Brain Res 1991 551 72 77 10.1016/0006-8993(91)90915-I 1655165 · DOI
  47. [49]Schliebs R Arendt T The cholinergic system in aging and neuronal degeneration Behav Brain Res 2011 221 555 563 10.1016/j.bbr.2010.11.058 21145918 · DOI · Paper page
  48. [50]Ferreira-Vieira TH Guimaraes IM Silva FR Ribeiro FM Alzheimer’s disease: Targeting the Cholinergic System Curr Neuropharmacol 2016 14 101 115 10.2174/1570159X13666150716165726 26813123 PMC4787279 · DOI · Paper page
  49. [51]Libeu CA Descamps O Zhang Q John V Bredesen DE Altering APP proteolysis: increasing sAPPalpha production by targeting dimerization of the APP ectodomain PLoS One 2012 7 e40027 10.1371/journal.pone.0040027 22768208 PMC3386930 · DOI
  50. [52]Nagai N Ito Y Excessive hydrogen peroxide enhances the attachment of amyloid beta1-42 in the lens epithelium of UPL rats, a hereditary model for cataracts Toxicology 2014 315 55 64 10.1016/j.tox.2013.08.003 23941810 · DOI
  51. [53]Sezgin B Disulfiram Implantation for the Treatment of Alcoholism: Clinical Experiences from the Plastic Surgeon’s Point of View Arch Plast Surg. 2014 41 571 575 10.5999/aps.2014.41.5.571 25276651 PMC4179363 · DOI
  52. [54]Wang Z Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells Nanomedicine 2017 13 641 657 10.1016/j.nano.2016.08.001 27521693 PMC5364371 · DOI
  53. [55]Nagai N Mano Y Ito Y An Ophthalmic Formulation of Disulfiram Nanoparticles Prolongs Drug Residence Time in Lens Biol Pharm Bull 2016 39 1881 1887 10.1248/bpb.b16-00592 27803460 · DOI
  54. [56]Endres K Transnasal delivery of human A-beta peptides elicits impaired learning and memory performance in wild type mice BMC Neurosci 2016 17 44 10.1186/s12868-016-0280-9 27377996 PMC4932715 · DOI
  55. [57]Reinhardt S Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer’s disease FASEB J 2014 28 978 997 10.1096/fj.13-234864 24165480 · DOI
  56. [58]Steiner H Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases Nat Cell Biol 2000 2 848 851 10.1038/35041097 11056541 · DOI
  57. [59]Deacon RM Assessing nest building in mice Nat Protoc 2006 1 1117 1119 10.1038/nprot.2006.170 17406392 · DOI
  58. [60]Schneider CA Rasband WS Eliceiri KW NIH Image to ImageJ: 25 years of image analysis Nat Methods 2012 9 671 675 10.1038/nmeth.2089 22930834 PMC5554542 · DOI · Paper page

Authors
Reinhardt, S., Stoye, N., Luderer, M., Kiefer, F., Schmitt, U., Lieb, K., & Endres, K.
Affiliations
  • Johannes Gutenberg University Mainz (DE)
  • Heidelberg University (DE)
Corresponding author
Endres, Kristina
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2018-01-22
Volume
8
Issue
1
Pages
1329-1329
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-018-19577-7
PMC
PMC5778060
OpenAlex
W2783453358
Cited by
58
References
61
Citations by year
2026: 8 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 1
FWCI
3.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Gutenberg Open Science (submittedVersion, cc-by-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Gutenberg Open Science (cc-by)
Funders
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
disulfiram, ADAM10, Alzheimer's disease, alpha-secretase, amyloid precursor protein, amyloid-beta aggregation, amyloid plaques, drug repurposing, dentate gyrus, learning and memory impairment, peripheral blood cells, alcoholism
MeSH terms
ADAM10 Protein, Alzheimer Disease, Animals, Disulfiram, Humans, Male, Membrane Proteins, Mice, Inbred C57BL, Dentate Gyrus, Cell Line, Tumor, Mice, Amyloid Precursor Protein Secretases

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