Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy

Redox Biology
Ana I RojoAntonio Cuadrado

Abstract

Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspected to participate in the neurodegenerative process. Transcription factor NRF2, a master regulator of redox homeostasis, controls acute inflammation but its relevance in low-grade chronic inflammation of AD is inconclusive due to lack of good mouse models. We have addressed this question in a transgenic mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-WT mice died prematurely, at around 14 months of age, due to motor deficits and a terminal spinal deformity but AT-NRF2-KO mice died roughly 2 months earlier. NRF2-deficiency correlated with exacerbated astrogliosis and microgliosis, as determined by an increase in GFAP, IBA1 and CD11b levels. The immunomodulatory molecule dimethyl fumarate (DMF), a drug already used for the treatment of multiple sclerosis whose main target is accepted to be NRF2, was tested in this preclinical model. Daily oral gavage of DMF during six weeks reduced glial and inflammatory markers and improved cognition and motor complications in the AT-NRF2-WT mice compared with the vehicle-treated an...Continue Reading

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Citations

Dec 28, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Debra L LaskinJeffrey D Laskin
Mar 21, 2019·Journal of Cellular and Molecular Medicine·Lingbo KongDingjun Hao
Jan 23, 2020·ASN Neuro·Mikah S Brandes, Nora E Gray
Jul 25, 2019·International Journal of Molecular Sciences·Farzane SivandzadeLuca Cucullo
Jan 15, 2020·Molecular and Cellular Biology·Akira UrunoMasayuki Yamamoto
Jan 6, 2019·Nature Reviews. Drug Discovery·Antonio CuadradoAlbena T Dinkova-Kostova
Aug 7, 2019·Cellular and Molecular Neurobiology·M Galán-GangaI Lastres-Becker
Aug 30, 2020·Pharmacological Reviews·Ana I CasasHarald H H W Schmidt
Dec 6, 2020·International Journal of Molecular Sciences·Rafael Gonzalo-GobernadoEulalia Bazán
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Feijie ZhaoSongling Zhang
Jul 1, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Veerta SharmaThakur Gurjeet Singh
Jul 28, 2021·Free Radical Biology & Medicine·J Jiménez-VillegasA I Rojo

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Methods Mentioned

BETA
PCR
PCRs
X-ray

Software Mentioned

GraphPad Prism

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