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

Fiona Kerr, Oyinkan Sofola-Adesakin, Dobril K. Ivanov, Jemma Gatliff, Beatriz Gomez Perez-Nievas, Helene C. Bertrand, Pedro Martinez, Rebecca Callard, Inge Snoeren, Helena M. Cocheme, Jennifer Adcott, Mobina Khericha, Jorge Ivan Castillo-Quan, Geoffrey Wells, Wendy Noble, Janet Thornton, Linda Partridge

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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 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 re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.
Original languageEnglish
JournalPLoS Genetics
Volume13
Issue number3
DOIs
Publication statusPublished - 2 Mar 2017

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Alzheimer disease
Alzheimer Disease
toxicity
therapeutics
inhibitor
Glycogen Synthase Kinase 3
Cytoprotection
lithium
Drug Design
disease prevention
neurodegenerative diseases
Lithium
Neurodegenerative Diseases
Therapeutics
neurons
adverse effects
peptides
Neurons
drugs
reactivation

Keywords

  • Alzheimer's disease
  • neurodegenerative diseases
  • Nrf2
  • Keap1

Cite this

Kerr, F., Sofola-Adesakin, O., Ivanov, D. K., Gatliff, J., Perez-Nievas, B. G., Bertrand, H. C., ... Partridge, L. (2017). Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease. PLoS Genetics, 13(3). https://doi.org/10.1371/journal.pgen.1006593
Kerr, Fiona ; Sofola-Adesakin, Oyinkan ; Ivanov, Dobril K. ; Gatliff, Jemma ; Perez-Nievas, Beatriz Gomez ; Bertrand, Helene C. ; Martinez, Pedro ; Callard, Rebecca ; Snoeren, Inge ; Cocheme, Helena M. ; Adcott, Jennifer ; Khericha, Mobina ; Castillo-Quan, Jorge Ivan ; Wells, Geoffrey ; Noble, Wendy ; Thornton, Janet ; Partridge, Linda. / Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease. In: PLoS Genetics. 2017 ; Vol. 13, No. 3.
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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 A{\ss}42 peptide, in correlation with Nrf2 activation. Comparatively, lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented A{\ss}42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived A{\ss} 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.",
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author = "Fiona Kerr and Oyinkan Sofola-Adesakin and Ivanov, {Dobril K.} and Jemma Gatliff and Perez-Nievas, {Beatriz Gomez} and Bertrand, {Helene C.} and Pedro Martinez and Rebecca Callard and Inge Snoeren and Cocheme, {Helena M.} and Jennifer Adcott and Mobina Khericha and Castillo-Quan, {Jorge Ivan} and Geoffrey Wells and Wendy Noble and Janet Thornton and Linda Partridge",
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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 2017, 'Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease', PLoS Genetics, vol. 13, no. 3. https://doi.org/10.1371/journal.pgen.1006593

Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease. / Kerr, Fiona; Sofola-Adesakin, Oyinkan; Ivanov, Dobril K. ; Gatliff, Jemma; Perez-Nievas, Beatriz Gomez; Bertrand, Helene C.; Martinez, Pedro; Callard, Rebecca; Snoeren, Inge; Cocheme, Helena M.; Adcott, Jennifer; Khericha, Mobina; Castillo-Quan, Jorge Ivan; Wells, Geoffrey; Noble, Wendy; Thornton, Janet; Partridge, Linda.

In: PLoS Genetics, Vol. 13, No. 3, 02.03.2017.

Research output: Contribution to journalArticle

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AU - Kerr, Fiona

AU - Sofola-Adesakin, Oyinkan

AU - Ivanov, Dobril K.

AU - Gatliff, Jemma

AU - Perez-Nievas, Beatriz Gomez

AU - Bertrand, Helene C.

AU - Martinez, Pedro

AU - Callard, Rebecca

AU - Snoeren, Inge

AU - Cocheme, Helena M.

AU - Adcott, Jennifer

AU - Khericha, Mobina

AU - Castillo-Quan, Jorge Ivan

AU - Wells, Geoffrey

AU - Noble, Wendy

AU - Thornton, Janet

AU - Partridge, Linda

N1 - Acceptance date from VoT Applied Gold exception as published immediate OA in OA journal. ET 19/12/19 Funding note: FK and LP and are funded by Alzheimer’s Research UK (ARUK; ART-2009-4). BGPN is an ARUK Junior Research Fellow. OSA is an Alzheimer’s Society Senior Research Fellow. This work was also supported by a Wellcome Trust Strategic Award to LP (WT098565/Z/12/Z) and the Max Planck Institute for the Biology of Ageing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2017/3/2

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N2 - 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 re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.

AB - 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 re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.

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KW - neurodegenerative diseases

KW - Nrf2

KW - Keap1

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DO - 10.1371/journal.pgen.1006593

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Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Perez-Nievas BG, Bertrand HC et al. Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease. PLoS Genetics. 2017 Mar 2;13(3). https://doi.org/10.1371/journal.pgen.1006593