Role of NRF2 in Pathogenesis of Alzheimer's Disease

Overview

Journal Antioxidants (Basel)

Date 2025 Jan 8

PMID 39765857

Authors

Ching-Tung Chu

Akira Uruno

Fumiki Katsuoka

Masayuki Yamamoto

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is a polygenic, multifactorial neurodegenerative disorder and remains the most prevalent form of dementia, globally. Despite decades of research efforts, there is still no effective cure for this debilitating condition. AD research has increasingly focused on transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) as a potential therapeutic target. NRF2 plays a crucial role in protecting cells and tissues from environmental stressors, such as electrophiles and reactive oxygen species. Recently, an increasing number of studies have demonstrated that NRF2 is a key regulator in AD pathology. NRF2 is highly expressed in microglia, resident macrophages in the central nervous system, and contributes to neuroinflammation, phagocytosis and neurodegeneration in AD. NRF2 has been reported to modulate microglia-induced inflammation and facilitate the transition from homeostatic microglia to a disease-associated microglia subset. Genetic and pharmacological activation of NRF2 has been demonstrated to improve cognitive function. Here, we review the current understanding of the involvement of NRF2 in AD and the critical role that NRF2 plays in microglia in the context of AD. Our aim is to highlight the potential of targeting NRF2 in the microglia as a promising therapeutic strategy for mitigating the progression of AD.

References

Mayer C, Riera-Ponsati L, Kauppinen S, Klitgaard H, Erler J, Hansen S . Targeting the NRF2 pathway for disease modification in neurodegenerative diseases: mechanisms and therapeutic implications. Front Pharmacol. 2024; 15:1437939. PMC: 11306042. DOI: 10.3389/fphar.2024.1437939. View

Thimmulappa R, Lee H, Rangasamy T, Reddy S, Yamamoto M, Kensler T . Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest. 2006; 116(4):984-95. PMC: 1421348. DOI: 10.1172/JCI25790. View

Li Q, Cheng Z, Zhou L, Darmanis S, Neff N, Okamoto J . Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing. Neuron. 2019; 101(2):207-223.e10. PMC: 6336504. DOI: 10.1016/j.neuron.2018.12.006. View

Sheppard O, Coleman M, Durrant C . Lipopolysaccharide-induced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta. J Neuroinflammation. 2019; 16(1):106. PMC: 6525970. DOI: 10.1186/s12974-019-1490-8. View

Milanesi E, Dobre M, Cucos C, Rojo A, Jimenez-Villegas J, Capetillo-Zarate E . Whole Blood Expression Pattern of Inflammation and Redox Genes in Mild Alzheimer's Disease. J Inflamm Res. 2021; 14:6085-6102. PMC: 8612672. DOI: 10.2147/JIR.S334337. View

Rangasamy T, Guo J, Mitzner W, Roman J, Singh A, Fryer A . Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005; 202(1):47-59. PMC: 2212893. DOI: 10.1084/jem.20050538. View

Kim H, Yun Kim H, Ehrlich H, Choi S, Kim D, Kim Y . Amelioration of Alzheimer's disease by neuroprotective effect of sulforaphane in animal model. Amyloid. 2012; 20(1):7-12. DOI: 10.3109/13506129.2012.751367. View

Liang C, Liu L, Bao S, Yao Z, Bai Q, Fu P . Neuroprotection by Nrf2 via modulating microglial phenotype and phagocytosis after intracerebral hemorrhage. Heliyon. 2023; 9(2):e13777. PMC: 9957781. DOI: 10.1016/j.heliyon.2023.e13777. View

Chen X, Dodd G, Thomas S, Zhang X, Wasserman M, Rovin B . Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol. 2005; 290(5):H1862-70. DOI: 10.1152/ajpheart.00651.2005. View

10.

Yamamoto M, Kensler T, Motohashi H . The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiol Rev. 2018; 98(3):1169-1203. PMC: 9762786. DOI: 10.1152/physrev.00023.2017. View

11.

Cuadrado A, Rojo A, Wells G, Hayes J, Cousin S, Rumsey W . Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019; 18(4):295-317. DOI: 10.1038/s41573-018-0008-x. View

12.

Sun J, Hu H, Ren X, Simpkins J . Tert-butylhydroquinone compromises survival in murine experimental stroke. Neurotoxicol Teratol. 2016; 54:15-21. PMC: 4789102. DOI: 10.1016/j.ntt.2016.01.004. View

13.

Dringen R, Pfeiffer B, Hamprecht B . Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci. 1999; 19(2):562-9. PMC: 6782200. View

14.

Hayes J, Flanagan J, Jowsey I . Glutathione transferases. Annu Rev Pharmacol Toxicol. 2005; 45:51-88. DOI: 10.1146/annurev.pharmtox.45.120403.095857. View

15.

Chanas S, Jiang Q, McMahon M, McWalter G, McLellan L, Elcombe C . Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem J. 2002; 365(Pt 2):405-16. PMC: 1222698. DOI: 10.1042/BJ20020320. View

16.

Tebay L, Robertson H, Durant S, Vitale S, Penning T, Dinkova-Kostova A . Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med. 2015; 88(Pt B):108-146. PMC: 4659505. DOI: 10.1016/j.freeradbiomed.2015.06.021. View

17.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland T . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017; 169(7):1276-1290.e17. DOI: 10.1016/j.cell.2017.05.018. View

18.

Lim P, Duarte T, Arezes J, Garcia-Santos D, Hamdi A, Pasricha S . Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin. Nat Metab. 2019; 1(5):519-531. PMC: 6609153. DOI: 10.1038/s42255-019-0063-6. View

19.

Kuga A, Tsuchida K, Panda H, Horiuchi M, Otsuki A, Taguchi K . The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation . Mol Cell Biol. 2022; 42(7):e0056321. PMC: 9302178. DOI: 10.1128/mcb.00563-21. View

20.

Damulina A, Pirpamer L, Soellradl M, Sackl M, Tinauer C, Hofer E . Cross-sectional and Longitudinal Assessment of Brain Iron Level in Alzheimer Disease Using 3-T MRI. Radiology. 2020; 296(3):619-626. DOI: 10.1148/radiol.2020192541. View