Imperial College London
Alternate

DrHelenaCocheme

Faculty of Medicine, Institute of Clinical Sciences

Honorary Senior Lecturer
 
 
 
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Contact

 

helena.cocheme Website

 
 
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Location

 

4.15ELMS BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Kerr:2017:10.1371/journal.pgen.1006593,
author = {Kerr, F and Sofola-Adesakin, O and Ivanov, DK and Gatliff, J and Perez-Nievas, BG and Bertrand, HC and Martinez, P and Callard, R and Snoeren, I and Cocheme, HM and Adcott, J and Khericha, M and Castillo-Quan, JI and Wells, G and Noble, W and Thornton, J and Partridge, L},
doi = {10.1371/journal.pgen.1006593},
journal = {PLoS Genetics},
title = {Direct Keap 1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease},
url = {http://dx.doi.org/10.1371/journal.pgen.1006593},
volume = {13},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target forthe prevention of neurodegenerative diseases, including Alzheimer’s disease (AD). CurrentNrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimentaleffects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerativeconditions may therefore direct the design of drugs targeted for the prevention ofthese diseases with minimal side-effects. Our study provides the first in vivo evidence thatspecific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity inresponse 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 mechanismsindependent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain alsoprevented synaptotoxicity mediated by naturally-derived Aβ oligomers in mouse corticalneurons. Overall, our findings highlight Keap1 specifically as an efficient target for the reactivationof Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors forthe prevention of neurodegeneration in vivo.
AU  - Kerr,F
AU  - Sofola-Adesakin,O
AU  - Ivanov,DK
AU  - Gatliff,J
AU  - Perez-Nievas,BG
AU  - Bertrand,HC
AU  - Martinez,P
AU  - Callard,R
AU  - Snoeren,I
AU  - Cocheme,HM
AU  - Adcott,J
AU  - Khericha,M
AU  - Castillo-Quan,JI
AU  - Wells,G
AU  - Noble,W
AU  - Thornton,J
AU  - Partridge,L
DO  - 10.1371/journal.pgen.1006593
PY  - 2017///
SN  - 1553-7390
TI  - Direct Keap 1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease
T2  - PLoS Genetics
UR  - http://dx.doi.org/10.1371/journal.pgen.1006593
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000398043000054&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/49459
VL  - 13
ER  -
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