NeuroMolecular Medicine

, Volume 21, Issue 1, pp 1–11 | Cite as

Therapeutic Approaches to Alzheimer’s Disease Through Modulation of NRF2

  • Gahee Bahn
  • Dong-Gyu JoEmail author
Review Paper


The nuclear factor erythroid-derived 2-related factor 2 (NFE2L2/NRF2) is a master transcription factor that regulates oxidative stress-related genes containing the antioxidant response element (ARE) in their promoters. The damaged function and altered localization of NRF2 are found in most neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis. These neurodegenerative diseases developed from various risk factors such as accumulated oxidative stress and genetic and environmental elements. NRF2 activation protects our bodies from detrimental stress by upregulating antioxidative defense pathway, inhibiting inflammation, and maintaining protein homeostasis. NRF2 has emerged as a new therapeutic target in AD. Indeed, recent studies revealed that NRF2 activators have therapeutic effects in AD animal models and in cultured human cells that express AD pathology. This review will focus on the NRF2 pathway and the role of NRF2 in AD and suggest some NRF2 inducers as therapeutic agents for AD.


NRF2 NRF2 activator Alzheimer’s disease Amyloid-β Oxidative stress ROS Neurodegenerative disease 



This work was supported by Grants (2012R1A5A2A28671860, 2017M3C7A1048268, 2018M3C7A1021851) funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF), the Ministry of Education, Science and Technology, Republic of Korea.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interests.


  1. Alumkal, J. J., Slottke, R., Schwartzman, J., Cherala, G., Munar, M., Graff, J. N., et al. (2015). A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer. Investigational New Drugs, 33(2), 480–489.Google Scholar
  2. Alzheimer’s Association. (2018). 2018 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 14(3), 367–429.Google Scholar
  3. Amin, F. U., Shah, S. A., & Kim, M. O. (2017). Vanillic acid attenuates Abeta1-42-induced oxidative stress and cognitive impairment in mice. Scientific Reports, 7, 40753.Google Scholar
  4. Baek, S. H., Park, S. J., Jeong, J. I., Kim, S. H., Han, J., Kyung, J. W., et al. (2017). Inhibition of Drp1 ameliorates synaptic depression, abeta deposition, and cognitive impairment in an Alzheimer’s disease model. The Journal of Neuroscience, 37(20), 5099–5110.Google Scholar
  5. Biogen Idec. (2013). Tecfidera (dimethyl fumarate): US prescribing information. Available at Accessed 20 October 2014.
  6. Bomprezzi, R. (2015). Dimethyl fumarate in the treatment of relapsing–remitting multiple sclerosis: An overview. Therapeutic Advances in Neurological Disorders, 8(1), 20–30.Google Scholar
  7. Bonda, D. J., Wang, X., Perry, G., Nunomura, A., Tabaton, M., Zhu, X., et al. (2010). Oxidative stress in Alzheimer disease: A possibility for prevention. Neuropharmacology, 59(4–5), 290–294.Google Scholar
  8. Branca, C., Ferreira, E., Nguyen, T.-V., Doyle, K., Caccamo, A., & Oddo, S. (2017). Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. Human Molecular Genetics, 26(24), 4823–4835.Google Scholar
  9. Brown, S. L., Sekhar, K. R., Rachakonda, G., Sasi, S., & Freeman, M. L. (2008). Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Research, 68(2), 364–368.Google Scholar
  10. Calkins, M. J., Johnson, D. A., Townsend, J. A., Vargas, M. R., Dowell, J. A., Williamson, T. P., et al. (2009). The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxidants & Redox Signaling, 11(3), 497–508.Google Scholar
  11. Chang, W. H., Chen, M. C., & Cheng, I. H. (2015). Antroquinonol lowers Brain Amyloid-beta levels and improves spatial learning and memory in a transgenic mouse model of Alzheimer’s disease. Scientific Reports, 5, 15067.Google Scholar
  12. Chin, M. P., Bakris, G. L., Block, G. A., Chertow, G. M., Goldsberry, A., Inker, L. A., et al. (2018). Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes: Post-hoc analyses from bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study. American Journal of Nephrology, 47(1), 40–47.Google Scholar
  13. Chin, M. P., Wrolstad, D., Bakris, G. L., Chertow, G. M., de Zeeuw, D., Goldsberry, A., et al. (2014). Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. Journal of Cardiac Failure, 20(12), 953–958.Google Scholar
  14. Cho, D.-H., Nakamura, T., Fang, J., Cieplak, P., Godzik, A., Gu, Z., et al. (2009). S-nitrosylation of Drp1 mediates β-amyloid-related mitochondrial fission and neuronal injury. Science, 324(5923), 102–105.Google Scholar
  15. Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A., & Hayes, J. D. (2013). Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene, 32(32), 3765.Google Scholar
  16. Congdon, E. E., & Sigurdsson, E. M. (2018). Tau-targeting therapies for Alzheimer disease. Nature Reviews Neurology, 14(7), 399–415.Google Scholar
  17. Cuadrado, A., Kugler, S., & Lastres-Becker, I. (2018). Pharmacological targeting of GSK-3 and NRF2 provides neuroprotection in a preclinical model of tauopathy. Redox Biology, 14, 522–534.Google Scholar
  18. Cui, Y., Ma, S., Zhang, C., Li, D., Yang, B., Lv, P., et al. (2018). Pharmacological activation of the Nrf2 pathway by 3H-1, 2-dithiole-3-thione is neuroprotective in a mouse model of Alzheimer disease. Behavioural Brain Research, 336, 219–226.Google Scholar
  19. De Zeeuw, D., Akizawa, T., Audhya, P., Bakris, G. L., Chin, M., Christ-Schmidt, H., et al. (2013). Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. New England Journal of Medicine, 369(26), 2492–2503.Google Scholar
  20. Dixit, R., Ross, J. L., Goldman, Y. E., & Holzbaur, E. L. (2008). Differential regulation of dynein and kinesin motor proteins by tau. Science, 319(5866), 1086–1089.Google Scholar
  21. Dumont, M., Wille, E., Calingasan, N. Y., Tampellini, D., Williams, C., Gouras, G. K., et al. (2009). Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer’s disease. Journal of Neurochemistry, 109(2), 502–512.Google Scholar
  22. European Medicines Agency. (2013). Summary of opinion (initial authorisation): Tecfidera. Available from: [cited 27 January 2014].
  23. Feng, Y., & Wang, X. (2012). Antioxidant therapies for Alzheimer’s disease. Oxidative Medicine and Cellular Longevity, 2012, 472932.Google Scholar
  24. Fragoulis, A., Siegl, S., Fendt, M., Jansen, S., Soppa, U., Brandenburg, L. O., et al. (2017). Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer’s disease. Redox Biology, 12, 843–853.Google Scholar
  25. Fujiwara, K. T., Kataoka, K., & Nishizawa, M. (1993). Two new members of the maf oncogene family, mafK and mafF, encode nuclear b-Zip proteins lacking putative trans-activator domain. Oncogene, 8(9), 2371–2380.Google Scholar
  26. Giraldo, E., Lloret, A., Fuchsberger, T., & Viña, J. (2014). Aβ and tau toxicities in Alzheimer’s are linked via oxidative stress-induced p38 activation: Protective role of vitamin E. Redox Biology, 2, 873–877.Google Scholar
  27. Grundke-Iqbal, I., Iqbal, K., Tung, Y.-C., Quinlan, M., Wisniewski, H. M., & Binder, L. I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proceedings of the National Academy of Sciences USA, 83(13), 4913–4917.Google Scholar
  28. Gwon, A. R., Park, J. S., Arumugam, T. V., Kwon, Y. K., Chan, S. L., Kim, S. H., et al. (2012). Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer’s disease. Aging Cell, 11(4), 559–568.Google Scholar
  29. He, C. H., Gong, P., Hu, B., Stewart, D., Choi, M. E., Choi, A. M., et al. (2001). Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. Journal of Biological Chemistry, 276(24), 20858–20865.Google Scholar
  30. Hinoi, E., Fujimori, S., Wang, L., Hojo, H., Uno, K., & Yoneda, Y. (2006). Nrf2 negatively regulates osteoblast differentiation via interfering with Runx2-dependent transcriptional activation. Journal of Biological Chemistry, 281(26), 18015–18024.Google Scholar
  31. Hu, C., Eggler, A. L., Mesecar, A. D., & Van Breemen, R. B. (2011). Modification of keap1 cysteine residues by sulforaphane. Chemical Research in Toxicology, 24(4), 515–521.Google Scholar
  32. Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., et al. (1997). An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochemical and Biophysical Research Communications, 236(2), 313–322.Google Scholar
  33. Jazwa, A., Rojo, A. I., Innamorato, N. G., Hesse, M., Fernández-Ruiz, J., & Cuadrado, A. (2011). Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxidants & Redox Signaling, 14(12), 2347–2360.Google Scholar
  34. Jiao, W., Wang, Y., Kong, L., Ou-Yang, T., Meng, Q., Fu, Q., et al. (2018). CART peptide activates the Nrf2/HO-1 antioxidant pathway and protects hippocampal neurons in a rat model of Alzheimer’s disease. Biochemical and Biophysical Research Communications, 501(4), 1016–1022.Google Scholar
  35. Jing, X., Shi, H., Zhang, C., Ren, M., Han, M., Wei, X., et al. (2015). Dimethyl fumarate attenuates 6-OHDA-induced neurotoxicity in SH-SY5Y cells and in animal model of Parkinson’s disease by enhancing Nrf2 activity. Journal of Neuroscience, 286, 131–140.Google Scholar
  36. Jo, C., Gundemir, S., Pritchard, S., Jin, Y. N., Rahman, I., & Johnson, G. V. (2014). Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nature Communications, 5, 3496.Google Scholar
  37. Jo, D.-G., Arumugam, T. V., Woo, H.-N., Park, J.-S., Tang, S.-C., Mughal, M., et al. (2010). Evidence that γ-secretase mediates oxidative stress-induced β-secretase expression in Alzheimer’s disease. Neurobiology of Aging, 31(6), 917–925.Google Scholar
  38. Johnson, D. A., & Johnson, J. A. (2015). Nrf2—a therapeutic target for the treatment of neurodegenerative diseases. Free Radical Biology & Medicine, 88, 253–267.Google Scholar
  39. Joshi, G., Gan, K. A., Johnson, D. A., & Johnson, J. A. (2015). Increased Alzheimer’s disease–like pathology in the APP/PS1∆E9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiology of Aging, 36(2), 664–679.Google Scholar
  40. Kanninen, K., Heikkinen, R., Malm, T., Rolova, T., Kuhmonen, S., Leinonen, H., et al. (2009). Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences USA, 106(38), 16505–16510.Google Scholar
  41. Kanninen, K., Malm, T. M., Jyrkkänen, H.-K., Goldsteins, G., Keksa-Goldsteine, V., Tanila, H., et al. (2008). Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Molecular Cellular Neuroscience, 39(3), 302–313.Google Scholar
  42. Karuppagounder, S. S., Xu, H., Shi, Q., Chen, L. H., Pedrini, S., Pechman, D., et al. (2009). Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer’s mouse model. Neurobiology of Aging, 30(10), 1587–1600.Google Scholar
  43. Katoh, Y., Itoh, K., Yoshida, E., Miyagishi, M., Fukamizu, A., & Yamamoto, M. (2001). Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes to Cells, 6(10), 857–868.Google Scholar
  44. Keleku-Lukwete, N., Suzuki, M., & Yamamoto, M. (2017). An overview of the advantages of KEAP1-NRF2 system activation during inflammatory disease treatment. Antioxidants & Redox Signaling, 29(17), 1746–1755.Google Scholar
  45. Kim, H. V., Kim, H. Y., Ehrlich, H. Y., Choi, S. Y., Kim, D. J., & Kim, Y. (2013a). Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model. Amyloid, 20(1), 7–12.Google Scholar
  46. Kim, J.-H., Yu, S., Chen, J. D., & Kong, A. (2013b). The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains. Oncogene, 32(4), 514.Google Scholar
  47. Kim, S., Choi, K. J., Cho, S. J., Yun, S. M., Jeon, J. P., Koh, Y. H., et al. (2016). Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors. Scientific Reports, 6, 24933.Google Scholar
  48. Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., et al. (2004). Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Molecular and Cellular Biology, 24(16), 7130–7139.Google Scholar
  49. Kubben, N., Zhang, W., Wang, L., Voss, T. C., Yang, J., Qu, J., et al. (2016). Repression of the antioxidant NRF2 pathway in premature aging. Cell, 165(6), 1361–1374.Google Scholar
  50. Lastres-Becker, I., García-Yagüe, A. J., Scannevin, R. H., Casarejos, M. J., Kügler, S., Rábano, A., et al. (2016). Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s disease. Antioxidants & Redox Signaling, 25(2), 61–77.Google Scholar
  51. Lastres-Becker, I., Innamorato, N. G., Jaworski, T., Rabano, A., Kugler, S., Van Leuven, F., et al. (2014). Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis. Brain, 137(Pt 1), 78–91.Google Scholar
  52. Li, Z., Chen, X., Zhang, Y., Liu, X., Wang, C., Teng, L., et al. (2018). Protective roles of Amanita caesarea polysaccharides against Alzheimer’s disease via Nrf2 pathway. International Journal of Biological Macromolecules, 121, 29–37.Google Scholar
  53. Liby, K., Hock, T., Yore, M. M., Suh, N., Place, A. E., Risingsong, R., et al. (2005). The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Research, 65(11), 4789–4798.Google Scholar
  54. Lin, M. T., & Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 443(7113), 787–795.Google Scholar
  55. Lindwall, G., & Cole, R. D. (1984). Phosphorylation affects the ability of tau protein to promote microtubule assembly. Journal of Biological Chemistry, 259(8), 5301–5305.Google Scholar
  56. Lipton, S. A., Rezaie, T., Nutter, A., Lopez, K. M., Parker, J., Kosaka, K., et al. (2016). Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer’s disease models. Cell Death & Disease. 7(12), e2499.Google Scholar
  57. Liu, P., Rojo de la Vega, M., Sammani, S., Mascarenhas, J. B., Kerins, M., Dodson, M., et al. (2018). RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE-dependent repression. Proceedings of the National Academy of Sciences USA, 115(44), e10352–e10361.Google Scholar
  58. Liu, Y., Deng, Y., Liu, H., Yin, C., Li, X., & Gong, Q. (2016). Hydrogen sulfide ameliorates learning memory impairment in APP/PS1 transgenic mice: A novel mechanism mediated by the activation of Nrf2. Pharmacology Biochemistry and Behavior, 150–151, 207–216.Google Scholar
  59. Liu, Z., Zhou, T., Ziegler, A. C., Dimitrion, P., & Zuo, L. (2017). Oxidative stress in neurodegenerative diseases: From molecular mechanisms to clinical applications. Oxidative Medicine and Cellular Longevity. Scholar
  60. McMahon, M., Thomas, N., Itoh, K., Yamamoto, M., & Hayes, J. D. (2004). Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. Journal of Biological Chemistry, 279(30), 31556–31567.Google Scholar
  61. Moi, P., Chan, K., Asunis, I., Cao, A., & Kan, Y. W. (1994). Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proceedings of the National Academy of Sciences USA, 91(21), 9926–9930.Google Scholar
  62. Murphy, K. E., Llewellyn, K., Wakser, S., Pontasch, J., Samanich, N., Flemer, M., et al. (2018). Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system. Journal of Biological Chemistry, 293(47), 18242–18269.Google Scholar
  63. Niino, M., Ohashi, T., Ochi, H., Nakashima, I., Shimizu, Y., & Matsui, M. (2018). Japanese guidelines for dimethyl fumarate. Clinical and Experimental Neuroimmunology, 9(4), 235–243.Google Scholar
  64. Nioi, P., Nguyen, T., Sherratt, P. J., & Pickett, C. B. (2005). The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Molecular and Cellular Biology, 25(24), 10895–10906.Google Scholar
  65. Rada, P., Rojo, A. I., Chowdhry, S., McMahon, M., Hayes, J. D., & Cuadrado, A. (2011). SCF (beta-TrCP) promotes Glycogen synthase kinase-3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Molecular and Cellular Biology, 31(6), 1121–1133.Google Scholar
  66. Raina, A. K., Templeton, D. J., Deak, J. C., Perry, G., & Smith, M. A. (1999). Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer’s disease. Redox Report, 4(1–2), 23–27.Google Scholar
  67. Ramsey, C. P., Glass, C. A., Montgomery, M. B., Lindl, K. A., Ritson, G. P., Chia, L. A., et al. (2007). Expression of Nrf2 in neurodegenerative diseases. Journal of Neuropathology & Experimental Neurology, 66(1), 75–85.Google Scholar
  68. René, C., Lopez, E., Claustres, M., Taulan, M., & Romey-Chatelain, M., C (2010). NF-E2-related factor 2, a key inducer of antioxidant defenses, negatively regulates the CFTR transcription. Cellular and Molecular Life Sciences, 67(13), 2297–2309.Google Scholar
  69. Rojo, A. I., Pajares, M., Rada, P., Nunez, A., Nevado-Holgado, A. J., Killik, R., et al. (2017). NRF2 deficiency replicates transcriptomic changes in Alzheimer’s patients and worsens APP and TAU pathology. Redox Biology, 13, 444–451.Google Scholar
  70. Saito, R., Suzuki, T., Hiramoto, K., Asami, S., Naganuma, E., Suda, H., et al. (2016). Characterizations of three major cysteine sensors of Keap1 in stress response. Molecular and Cellular Biology, 36(2), 271–284.Google Scholar
  71. SantaCruz, K. S., Yazlovitskaya, E., Collins, J., Johnson, J., & DeCarli, C. (2004). Regional NAD (P) H: Quinone oxidoreductase activity in Alzheimer’s disease. Neurobiology of Aging, 25(1), 63–69.Google Scholar
  72. Selkoe, D. J., & Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Molecular Medicine, 8(6), 595–608.Google Scholar
  73. Sherman, M. Y., & Goldberg, A. L. (2001). Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron, 29(1), 15–32.Google Scholar
  74. Smith, J. A., Das, A., Ray, S. K., & Banik, N. L. (2012). Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Research Bulletin, 87(1), 10–20.Google Scholar
  75. Suh, J. H., Shenvi, S. V., Dixon, B. M., Liu, H., Jaiswal, A. K., Liu, R.-M., et al. (2004). Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proceedings of the National Academy of Sciences USA, 101(10), 3381–3386.Google Scholar
  76. Sun, Y., Yang, T., Mao, L., & Zhang, F. (2017). Sulforaphane protects against brain diseases: Roles of cytoprotective enzymes. Austin Journal of Cerebrovascular Disease & Stroke 4(1), 1054.Google Scholar
  77. Sykiotis, G. P., & Bohmann, D. (2010). Stress-activated cap’n’collar transcription factors in aging and human disease. Science Signaling, 3(112), re3–re3.Google Scholar
  78. Tanji, K., Maruyama, A., Odagiri, S., Mori, F., Itoh, K., Kakita, A., et al. (2013). Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases. Journal of Neuropathology & Experimental Neurology, 72(1), 18–28.Google Scholar
  79. Tapias, V., Jainuddin, S., Ahuja, M., Stack, C., Elipenahli, C., Vignisse, J., et al. (2018). Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Human Molecular Genetics, 27(16), 2874–2892.Google Scholar
  80. Uttara, B., Singh, A. V., Zamboni, P., & Mahajan, R. (2009). Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Current Neuropharmacology, 7(1), 65–74.Google Scholar
  81. Venugopal, R., & Jaiswal, A. K. (1998). Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene, 17(24), 3145–3156.Google Scholar
  82. Vershinin, M., Carter, B. C., Razafsky, D. S., King, S. J., & Gross, S. P. (2007). Multiple-motor based transport and its regulation by Tau. Proceedings of the National Academy of Sciences USA, 104(1), 87–92.Google Scholar
  83. Wang, C. Y., Wang, Z. Y., Xie, J. W., Wang, T., Wang, X., Xu, Y., et al. (2016). Dl-3-n-butylphthalide-induced upregulation of antioxidant defense is involved in the enhancement of cross talk between CREB and Nrf2 in an Alzheimer’s disease mouse model. Neurobiology of Aging, 38, 32–46.Google Scholar
  84. Wang, H., Liu, K., Geng, M., Gao, P., Wu, X., Hai, Y., et al. (2013). RXRα Inhibits the NRF2-ARE signalling pathway through a direct interaction With the Neh7 domain of NRF2. Cancer Research, 73(10), 3097–3108.Google Scholar
  85. Wang, L., Wang, M., Hu, J., Shen, W., Hu, J., Yao, Y., et al. (2017). Protective effect of 3H-1, 2-dithiole-3-thione on cellular model of Alzheimer’s disease involves Nrf2/ARE signaling pathway. European Journal of Pharmacology, 795, 115–123.Google Scholar
  86. Wang, W., & Jaiswal, A. K. (2006). Nuclear factor Nrf2 and antioxidant response element regulate NRH:quinone oxidoreductase 2 (NQO2) gene expression and antioxidant induction. Free Radical Biology & Medicine, 40(7), 1119–1130.Google Scholar
  87. Wang, Y., Santa-Cruz, K., DeCarli, C., & Johnson, J. A. (2000). NAD (P) H: Quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Alzheimer’s disease. Neurobiology of Aging, 21(4), 525–531.Google Scholar
  88. Woo, H.-N., Park, J.-S., Gwon, A.-R., Arumugam, T. V., & Jo, D.-G. (2009). Alzheimer’s disease and notch signaling. Biochemical and Biophysical Research Communications, 390(4), 1093–1097.Google Scholar
  89. Wu, T., Zhao, F., Gao, B., Tan, C., Yagishita, N., Nakajima, T., et al. (2014). Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes & Development, 28(7), 708–722.Google Scholar
  90. Xie, G., Tian, W., Wei, T., & Liu, F. (2015). The neuroprotective effects of beta-hydroxybutyrate on Abeta-injected rat hippocampus in vivo and in Abeta-treated PC-12 cells in vitro. Free Radical Research, 49(2), 139–150.Google Scholar
  91. Yu, L., Wang, S., Chen, X., Yang, H., Li, X., Xu, Y., et al. (2015). Orientin alleviates cognitive deficits and oxidative stress in Abeta1-42-induced mouse model of Alzheimer’s disease. Life Sciences, 121, 104–109.Google Scholar
  92. Zhang, D. D., Lo, S.-C., Cross, J. V., Templeton, D. J., & Hannink, M. (2004). Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Molecular and Cellular Biology, 24(24), 10941–10953.Google Scholar
  93. Zhang, Y., Thompson, R., Zhang, H., & Xu, H. (2011). APP processing in Alzheimer’s disease. Molecular Brain, 4(1), 3.Google Scholar
  94. Zhou, Y., Xie, N., Li, L., Zou, Y., Zhang, X., & Dong, M. (2014). Puerarin alleviates cognitive impairment and oxidative stress in APP/PS1 transgenic mice. International Journal of Neuropsychopharmacology, 17(4), 635–644.Google Scholar
  95. Zhu, Y. F., Li, X. H., Yuan, Z. P., Li, C. Y., Tian, R. B., Jia, W., et al. (2015). Allicin improves endoplasmic reticulum stress-related cognitive deficits via PERK/Nrf2 antioxidative signaling pathway. European Journal of Pharmacology, 762, 239–246.Google Scholar
  96. Zuo, L., Zhou, T., Pannell, B., Ziegler, A., & Best, T. M. (2015). Biological and physiological role of reactive oxygen species—the good, the bad and the ugly. Acta Physiologica, 214(3), 329–348.Google Scholar

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Authors and Affiliations

  1. 1.School of PharmacySungkyunkwan UniversitySuwonRepublic of Korea
  2. 2.Department of Health Science and TechnologySamsung Advanced Institute for Health Science and Technology, Sungkyunkwan UniversitySeoulRepublic of Korea
  3. 3.Biomedical Institute for ConvergenceSungkyunkwan UniversitySuwonRepublic of Korea

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