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Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease.

Kerr, Fiona, Sofola-Adesakin, Oyinkan, Ivanov, Dobril K., Gatliff, Jemma, Gomez Perez-Nievas, Beatriz, Bertrand, Helene C., Martinez, Pedro, Callard, Rebecca, Snoeren, Inge, Cocheme, Helena M., Adcott, Jennifer, Khericha, Mobina, Castillo-Quan, Jorge Ivan and Partridge, Linda 2017. Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease. PLoS Genetics 13 (3) , e1006593. 10.1371/journal.pgen.1006593

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Public Library of Science
ISSN: 1553-7390
Date of First Compliant Deposit: 2 October 2019
Date of Acceptance: 21 January 2017
Last Modified: 02 Oct 2019 16:00

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