Jason Splawn

Introduction. Nrf2 is a transcription factor that regulates numerous genes involved in cytoprotective processes (1). Nrf2 decreases as a function of age and is also reduced in Alzheimer’s Disease patients, although the exact mechanism for this is unknown (1). Evidence indicates that oxidative stress increases as a function of age and detoxifying enzymes are reduced in Alzheimer’s Disease brains (4). These changes appear linked to a reduction in nuclear Nrf2 levels (4). One study showed that a reduction in Nrf2 exacerbates cognitive deficits in mouse models of Alzheimer’s Disease (1).  A second study suggests that Nrf2 plays a pivotal role in maintaining the appropriate expression levels of BAG3 and autophagy adaptor proteins during aging (2). A third study showed that LOF mutations in Keap1, which is a negative regulator of Nrf2, prevented neuronal toxicity against Aβ42 in correlation with increased Nrf2 activity (3). Methods. To determine the role of Nrf2 in APP/PS1 mice, Nrf2 knockout mice were tested via an open field test, Morris water maze, radial arm water maze, and contextual fear conditioning (1). The second study analyzed the brains of 4-, 8-, and 12-month WT and knockout mice for the expression of BAG3, autophagy adaptor proteins, and tau (2).  The third study used a Drosophila model to measure Aβ42 levels in response to LOF mutations in Keap1 (3).  Results. APP/SP1 mice performed significantly worse than WT mice but removing the Nrf2 gene exacerbated the difference (1).  Older Nrf2 knockout mice showed lower levels of BAG3 and autophagy adaptor proteins in the hippocampus and cortex, but elevated levels of phosphorylated tau (2). This suggests that Nrf2 regulates the processes that mediate tau clearance and increases in Nrf2 responsive genes during aging are likely to contribute to the maintenance of physiological levels of tau (2).  The Drosophila model was the first in-vivo evidence showing that Aβ42 inhibits activity of the fly homolog of Nrf2 (cncC) in neurons, consistent with previous findings in mice (3). LOF mutations in Keap1 protected against Aβ42 toxicity in this model (3).  Conclusions. These studies correlate Nrf2 dysfunction directly with cognitive deficits in Alzheimer’s Disease models (1-3). Also, Nrf2 appears to play a critical role in maintaining the expression levels of various cytoprotective proteins (1,2).  In addition, Keap1 could be an efficient target for the amelioration of Nrf2 deficits and protection against neuronal damage in Alzheimer’s Disease (3).

1. Branca C, Ferreira E, Nguyen T, Doyle K, Caccamo A, Oddo S. Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. Human Molecular Genetics. 2017;26(24):4823-4835
2. Tang M, Ji C, Pallo S, Rahman I, Johnson G. Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner. Neurobiology of Aging. 2018;63:128-139
3. Kerr F, Sofola-Adesakin O, Ivanov D, et al. Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease. PLoS Genetics. 2017;13(3):e1006593
4. Lipton S, Rezaie T, Nutter A, et al. Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer’s disease models. Cell Death & Disease. 2016;7:e2499