Nrf2 suppresses oxidative stress and inflammation in App knock-in Alzheimer’s disease model mice

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Uruno A, Matsumaru D, Ryoke R, Salto R, Kadoguchi S, Salgusa D, Salto T, Saldo TC, Kawashima R, and Yamamoto M. (2020) Nrf2 suppresses oxidative stress and inflammation in App knock-in Alzheimer’s disease model mice. Molecular Cell Biology, 40 (6)

Plasmalogens are a class of lipids that contain a vinyl-ether bond at sn-1 causing a more compact structure, giving these lipids characteristics that differ from other lipids. Plasmalogens provide protection from oxidative stress, are involved in membrane structure, and have an important role in vesicular fusion. Because of these roles, reduced levels of plasmalogens is associated with a number of disorders including rhizomelic chondrodysplasia punctata (RCDP), multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease (AD). AD is a neurodegenerative disorder most known for causing memory loss and cognitive decline. A single cause of AD is unlikely as many external and biochemical factors have been found to be associated with an increased risk of disease. Uruno et al investigated the role that NF-E2-related-factor (Nrf2), a transcription factor involved in stress response, had in AD pathology. This was accomplished by characterizing the pathology of a mouse model with a knock-down in the expression of Kelch-like ECH-associated protein 1 (Keap1). As the role of Keap1 is to degrade Nrf2, this model serves as a functional induction of the Nrf2 protein. As well, the mouse model expresses amyloid precursor protein (APP) that can be cleaved to produce beta-amyloid, a toxic protein associated with AD. Although they employed many analytical methods including real-time quantitative polymerase chain reaction, behavioral assays, histology, protein determination, and liquid chromatography-mass spectrometry (LC-MS), this blog will focus on their work studying plasmalogen levels within this AppNLGF::Keap1FA/FA model.

To determine whether plasmalogen phosphatidylethanolamine (PlsEtn) levels could be a biomarker for AD and the relationship between this type of lipid and Nrf2 in AD, plasmalogen levels were analyzed. A reduction in plasmalogen levels is known to occur in patients with AD, thus the first lipid analysis was used to characterize the plasmalogen levels within AppNLGF mice and wild-type mice to confirm this reduction. Of the 9 lipid species analyzed, PlsEtn 18:0/22:6 was significantly decreased from ~1800ng/mg in wildtype mice to ~1600 ng/mg AppNLGF mice, while PlsEtn 18:0/18:1 and 16:0/22:6 were also reduced compared to the wild-type mice, but were not found to be significantly different.

Matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to detect plasmalogens within the brain of AppNLGF mice and AppNLGF::Keap1FA/FAmice to determine if increased expression of Nrf2 rescues the plasmalogen reduction within the beta-amyloid-induced AD model. The coronal slices showed that PlsEtn 16:0/22:6 and 18:0/22:6 were decreased in the hypothalamus, thalamus, and hippocampus and PlsEtn 18:0/18:1 was decreased in the thalamus compared to the wild-type mice. Interestingly, when viewed in the double mutant, the plasmalogen levels were more comparable to the wild-type sections, indicating that Nrf2 activation was protective against the AD pathology caused by AppNLGF and recovered the plasmalogen levels.

Through the range of experiments conducted, Uruno et al found that the Nrf2 induction suppressed oxidative stress, inflammation, and reactive astrocytes caused by amyloid accumulation. Oxidative stress plays a significant role in the neurodegeneration present in AD and plasmalogens are known antioxidants, with the vinyl-ether bond being able to scavenge two radical oxygen species (ROS). Here is it shown that Nrf2 was able to suppress the effects of AppNLGF, including the reduced plasmalogen levels within the hypothalamus, thalamus, and hippocampus, the latter of which is involved in memory. The findings in this study suggest that the interaction between Keap1 and Nrf2 could be a new target for future drug treatments of AD, as Nrf2 activation was successful in reducing many areas of pathology typically seen in AD.