Abstract
| Original language | English |
|---|---|
| Journal | PLoS Genetics |
| Volume | 13 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2 Mar 2017 |
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Keywords
- Alzheimer's disease
- neurodegenerative diseases
- Nrf2
- Keap1
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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; 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 journal › Article
TY - JOUR
T1 - Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease
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
Y1 - 2017/3/2
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.
KW - Alzheimer's disease
KW - neurodegenerative diseases
KW - Nrf2
KW - Keap1
U2 - 10.1371/journal.pgen.1006593
DO - 10.1371/journal.pgen.1006593
M3 - Article
VL - 13
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 3
ER -