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Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease
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نویسنده
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kerr f. ,sofola-adesakin o. ,ivanov d.k. ,gatliff j. ,gomez perez-nievas b. ,bertrand h.c. ,martinez p. ,callard r. ,snoeren i. ,cochemé h.m. ,adcott j. ,khericha m. ,castillo-quan j.i. ,wells g. ,noble w. ,thornton j. ,partridge l.
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منبع
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plos genetics - 2017 - دوره : 13 - شماره : 3
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چکیده
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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. © 2017 kerr et al.
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آدرس
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institute of healthy ageing,and gee,university college london,darwin building,gower street,london,united kingdom,school of applied sciences,edinburgh napier university,9 sighthill court,edinburgh, United Kingdom, institute of healthy ageing,and gee,university college london,darwin building,gower street,london, United Kingdom, european molecular biology laboratory,european bioinformatics institute,wellcome trust genome campus,hinxton,cambridge, United Kingdom, ucl school of pharmacy,university college london,29/39 brunswick square,london, United Kingdom, maurice wohl clinical neuroscience institute,king’s college london,london, United Kingdom, ucl school of pharmacy,university college london,29/39 brunswick square,london, United Kingdom, institute of healthy ageing,and gee,university college london,darwin building,gower street,london, United Kingdom, institute of healthy ageing,and gee,university college london,darwin building,gower street,london,united kingdom,max planck institute for biology of ageing,köln, Germany, institute of healthy ageing,and gee,university college london,darwin building,gower street,london,united kingdom,max planck institute for biology of ageing,köln, Germany, mrc london institute of medical sciences,imperial college london,du cane road,london, United Kingdom, institute of healthy ageing,and gee,university college london,darwin building,gower street,london, United Kingdom, institute of healthy ageing,and gee,university college london,darwin building,gower street,london,united kingdom,max planck institute for biology of ageing,köln, Germany, institute of healthy ageing,and gee,university college london,darwin building,gower street,london,united kingdom,max planck institute for biology of ageing,köln, Germany, ucl school of pharmacy,university college london,29/39 brunswick square,london, United Kingdom, maurice wohl clinical neuroscience institute,king’s college london,london, United Kingdom, european molecular biology laboratory,european bioinformatics institute,wellcome trust genome campus,hinxton,cambridge, United Kingdom, institute of healthy ageing,and gee,university college london,darwin building,gower street,london,united kingdom,max planck institute for biology of ageing,köln, Germany
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Authors
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