title: Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease.
abstract: Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer's disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects. Our study provides the first in vivo evidence that specific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide, in correlation with Nrf2 activation. Comparatively, lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived Aβ oligomers in mouse cortical neurons. Overall, our findings highlight Keap1 specifically as an efficient target for the re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.
authors.forename: Fiona
authors.identifier: http://orcid.org/0000-0003-3097-1951
authors.initials: F
authors.lastname: Kerr
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.
authors.forename: Oyinkan
authors.initials: O
authors.lastname: Sofola-Adesakin
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Dobril K
authors.initials: DK
authors.lastname: Ivanov
authors.affiliation: UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London, United Kingdom.
authors.forename: Jemma
authors.initials: J
authors.lastname: Gatliff
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, London, United Kingdom.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gomez Perez-Nievas
authors.affiliation: UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London, United Kingdom.
authors.forename: Hélène C
authors.initials: HC
authors.lastname: Bertrand
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.
authors.forename: Pedro
authors.initials: P
authors.lastname: Martinez
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.|Max Planck Institute for Biology of Ageing, Köln, Germany.
authors.forename: Rebecca
authors.identifier: http://orcid.org/0000-0003-2538-4015
authors.initials: R
authors.lastname: Callard
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.|Max Planck Institute for Biology of Ageing, Köln, Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Snoeren
authors.affiliation: MRC London Institute of Medical Sciences, Imperial College London, Du Cane Road, London, United Kingdom.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Cochemé
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adcott
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.|Max Planck Institute for Biology of Ageing, Köln, Germany.
authors.forename: Mobina
authors.initials: M
authors.lastname: Khericha
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.|Max Planck Institute for Biology of Ageing, Köln, Germany.
authors.forename: Jorge Iván
authors.initials: JI
authors.lastname: Castillo-Quan
authors.affiliation: UCL School of Pharmacy, University College London, 29/39 Brunswick Square, London, United Kingdom.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Wells
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, King's College London, London, United Kingdom.
authors.forename: Wendy
authors.identifier: http://orcid.org/0000-0002-7898-4295
authors.initials: W
authors.lastname: Noble
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Janet
authors.initials: J
authors.lastname: Thornton
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, Darwin Building, Gower Street, London, United Kingdom.|Max Planck Institute for Biology of Ageing, Köln, Germany.
authors.forename: Linda
authors.identifier: http://orcid.org/0000-0001-9615-0094
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics* / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D008136:Longevity / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018613:Microscopy, Confocal; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013830:Thiadiazoles / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D016229:Amyloid beta-Peptides; D029721:Drosophila Proteins; C527886:Keap1 protein, Drosophila; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D010446:Peptide Fragments; D013830:Thiadiazoles; D014230:Triazoles; C075222:amyloid beta-protein (1-42); D009828:Oleanolic Acid; C445068:bardoxolone methyl; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride