Achucarro Seminars

25 May [2018]

at 13.00 CET

The transcription factor NRF2: a new brain protective strategy in Alzheimer's disease

Antonio Cuadrado

The Department of Biochemistry at Autonomous University of Madrid

Alzheimer's disease (AD) has been "cured" many times in preclinical models, but nevertheless all clinical trials continue to be ineffective. This fact indicates that the mere reproduction of amyloidopathy and tauopathy in mice provides an incomplete view of the disease. Our group considers that it is necessary to assess additional homeostatic deviations resulting from the loss of activity of the transcription factor NRF2, a crucial regulator of multiple stress responses whose activity decreases with aging. Through transcriptomic analysis we have observed that the brains of NRF2-knockout mice reproduce 7 and 10 of the most deregulated pathways of human aging and brains with AD, respectively. Based on this fact we have generated a mouse that combines amyloidopathy and tauopathy with the wild genotype (AT-NRF2-WT) or deficient in NRF2 (AT-NRF2-KO). AT-NRF2-KO brains  showed 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. The AT-NRF2-KO mice exhibited an early deficit in learning and spatial memory and the reduction of long-term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decrease with aging, such as the activity of NRF2, in the protection against proteotoxic, inflammatory and oxidative stress and provides a new strategy to combat AD.

Host: Fabio Cavaliere


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