The transcription factor Nrf2 is a central regulator of anti-inflammatory and antioxidant mechanisms that contribute to the development and progression of various neurological disorders. Although the direct and indirect Nrf2 regulatory roles on inflammation have been reviewed in recent years, the in vivo evidence of Nrf2 function on lipopolysaccharide (LPS)-induced cognitive decline and characteristic alterations of reactive microglia and astrocytes remains incomplete. During the 3–5 days after LPS or saline injection, 5–6-month-old wildtype (WT) and Nrf2−/− C57BL/6 mice were subjected to the novel object recognition task. Immunohistochemistry staining was employed for analyses of brain cells. The Nrf2−/− mice displayed exacerbated LPS-induced cognition impairment (28.1 ± 9.6% in the discrimination index of the novel object recognition task), enhanced hippocampal reactive microgliosis and astrogliosis, and an increased expression level of the water channel transmembrane protein aquaporin 4 when compared with WT controls. In addition, similar overt effects of Nrf2 deficiency on LPS-induced characteristic alterations of brain cells were observed in the cortex and striatum regions of mice. In summary, this transgenic loss-of-function study provides direct in vivo evidence that highlights the functional importance of Nrf2 activation in regulating LPS-induced cognitive alteration, glial responses, and aquaporin 4 expression. This finding provides a better understanding of the complex nature of Nrf2 signaling and neuroprotection.
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This study was supported in part by National Institutes of Health grants R01AT007429, R01NS046400, and R21NS110008 (SD) and the American Heart Association Postdoctoral Fellowship 16POST31220032 (LL).
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All procedures performed in studies involving animals were in accordance with the ethical standards of the National Institutes of Health Guide for the care and use of laboratory animals and approved by the Institutional Animal Care and Use Committee of the University of Florida (#201608068).
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Supplementary Fig. 1 Under basal conditions, the Nrf2−/− mice do not display an observable difference in the novel object recognition task. Both saline-treated wildtype (WT) and Nrf2−/− mice displayed a preference of exploration to the novel object compared with the familiar one, which were similar to the mixed group (combined with all saline-treated WT and Nrf2−/− mice; left panel; familiar vs. novel object; **P < 0.01, ***P < 0.001). Both post-saline groups displayed a very similar tendency in the discrimination index (middle panel). No significant difference was detected in the total exploration time of both objects among groups (right panel). There is no significant difference in the total exploration time between genotypes.
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Liu, L., Kelly, M.G., Yang, X.R. et al. Nrf2 Deficiency Exacerbates Cognitive Impairment and Reactive Microgliosis in a Lipopolysaccharide-Induced Neuroinflammatory Mouse Model. Cell Mol Neurobiol 40, 1185–1197 (2020). https://doi.org/10.1007/s10571-020-00807-4
- Aquaporin 4
- Novel object recognition
- Oxidative stress