Format

Send to

Choose Destination
Redox Biol. 2018 Sep;18:173-180. doi: 10.1016/j.redox.2018.07.006. Epub 2018 Jul 11.

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

Author information

1
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII. Instituto de Investigaciones Biomédicas "Alberto Sols", UAM-CSIC. Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of MadridMadrid, Spain. Electronic address: airojo@iib.uam.es.
2
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII. Instituto de Investigaciones Biomédicas "Alberto Sols", UAM-CSIC. Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of MadridMadrid, Spain.
3
Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina. Universidad Autónoma de Madrid, 28029. Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28029. Madrid, Spain.
4
Experimental Genetics Group-LEGTEGG, Department of Human Genetics, KU Leuven, Leuven, Belgium.
5
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
6
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII. Instituto de Investigaciones Biomédicas "Alberto Sols", UAM-CSIC. Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of MadridMadrid, Spain; Cellular and Molecular Medicine Department, Radiobiology Laboratory, "Victor Babes" National Institute of Pathology, Bucharest, Romania. Electronic address: antonio.cuadrado@uam.es.

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 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.

PMID:
30029164
PMCID:
PMC6052199
DOI:
10.1016/j.redox.2018.07.006
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center