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Direct Keap 1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease

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Title: Direct Keap 1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease
Authors: Kerr, F
Sofola-Adesakin, O
Ivanov, DK
Gatliff, J
Perez-Nievas, BG
Bertrand, HC
Martinez, P
Callard, R
Snoeren, I
Cocheme, HM
Adcott, J
Khericha, M
Castillo-Quan, JI
Wells, G
Noble, W
Thornton, J
Partridge, L
Item Type: Journal Article
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 reactivation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.
Issue Date: 2-Mar-2017
Date of Acceptance: 21-Jan-2017
URI: http://hdl.handle.net/10044/1/49459
DOI: https://dx.doi.org/10.1371/journal.pgen.1006593
ISSN: 1553-7390
Publisher: Public Library of Science
Journal / Book Title: PLoS Genetics
Volume: 13
Issue: 3
Copyright Statement: © 2017 Kerr et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GLYCOGEN-SYNTHASE KINASE-3
AMYOTROPHIC-LATERAL-SCLEROSIS
PROTEIN-PROTEIN INTERACTION
TRANSCRIPTION FACTOR NRF2
AMYLOID-BETA NEUROTOXICITY
OXIDATIVE STRESS
MOUSE MODEL
A-BETA
PARKINSONS-DISEASE
SIGNALING PATHWAY
0604 Genetics
Developmental Biology
Publication Status: Published
Article Number: ARTN e1006593
Appears in Collections:Clinical Sciences
Molecular Sciences



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