Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy
EntityUAM. Departamento de Bioquímica; UAM. Departamento de Farmacología; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); UAM. Instituto Teófilo Hernando de I+D del Medicamento (ITH); Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ); Instituto de Investigación del Hospital de La Princesa (IP)
10.1016/j.redox.2018.07.006Redox Biology 18 (2018): 173-180
Funded byThis work was funded by SAF2016-76520-R of the Spanish Ministry of Economy and Competitiveness, a Pathfinder grant of the Centres of Excellence in Neurodegeneration (COEN) of the EU-Joint Program for Neurodegenerative diseases, and European Regional Development Fund, Competitiveness Operational Program 2014–2020, through the grant P_37_732/2016 REDBRAIN and a collaborative CIBERNED project PI2017/04-3. M.P. is recipient of a FPU fellowship of Autonomous University of Madrid
ProjectGobierno de España. SAF2016-76520-R
SubjectsGene; Alzheimer disease; Brain - Phatology; Inflammation; Nf-E2-Related Factor 2; Tauopathies; Medicina
Rights© 2018 The Authors
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
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 animals. This study demonstrates the relevance of the inflammatory response in experimental AD, tightly regulated by NRF2 activity, and provides a new strategy to fight AD.
Google Scholar:Rojo Sanchís, Ana Isabel - Pajares, Marta - García-Yagüe, Angel J. - Buendia, Izaskun - Van Leuven, Fred - Yamamoto, Masayuki - López G., Manuela - Cuadrado Pastor, Antonio
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