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Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.

Original publication

DOI

10.1016/j.redox.2017.07.006

Type

Journal article

Journal

Redox biology

Publication Date

10/2017

Volume

13

Pages

444 - 451

Addresses

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 Madrid, Madrid, Spain. Electronic address: airojo@iib.uam.es.