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

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posted on 2023-06-09, 08:33 authored by Fiona Kerr, Oyinkan Adesakin, Dobril Ivanov, Jemma Gatliff, Beatriz Perez-Nievas, Helene Betrand, Pedro Martinez, Rebecca Callard, Inge Snoeren, Helena Cocheme, Jennifer Adcott, Mobina Khericha, Jorge Castillo-Quan, Geoffrey Wells, Noble Wendy, Thorton Janet, Partridge Linda
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 Aß42 peptide, in correlation with Nrf2 activation. Comparatively, lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aß42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived Aß 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.

History

Publication status

  • Published

File Version

  • Published version

Journal

PLoS Genetics

ISSN

1553-7390

Publisher

Public Library of Science

Issue

3

Volume

13

Page range

1-30

Article number

e1006593

Department affiliated with

  • Neuroscience Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-11-02

First Open Access (FOA) Date

2017-11-02

First Compliant Deposit (FCD) Date

2017-11-01

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