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2000
Volume 25, Issue 4
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Alzheimer’s disease (AD) is an age-dependent neurodegenerative disorder and the leading cause of dementia. AD is characterized by the aggregation of amyloid-ß (Aß) peptide, increased levels of tau protein, and loss of redox homeostasis responsible for mitochondrial dysfunction, oxidative stress, and neuroinflammation. Excessive accumulation of toxic Aß plaques activates microglia, which initiates neuroinflammation and consequently accelerates synaptic damage and neuronal loss. Various pro-inflammatory cytokines release, microglia proliferation, reactive astrocyte, and oxidative (reactive oxygen species (ROS) production, level of antioxidant enzymes, redox homeostasis, and lipid peroxidation) stress play a major role in AD. Several studies revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox homeostasis and works as an anti-inflammatory in various neurodegenerative disorders. D-Glutamate expression of transcription factor Nrf2 and its genes (glutamate-cysteine ligase catalytic subunit (GCLC), Heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase I (NQO1)) has been found in AD. Nrf2-HO-1 enhances the expression of antioxidant genes, inhibits microglia-mediated inflammation, and boosts mitochondrial function, suggesting that modulators of this protein may be useful to manage AD. This review focuses on the role of Nrf2 in AD, with a particular emphasis on the various pathways involved in the positive and negative modulation of Nrf2, namely Phos-phoinositide 3-kinase (PI3K), Glycogen synthase kinase-3 (GSK-3), Nuclear factor kappa-B (NF-κB), and p38Mitogen-activated protein kinases (p38MAPK). Also, we have discussed the progress and challenges regarding the Nrf2 activators for AD treatment.

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/content/journals/cmm/10.2174/1566524023666230726145447
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Role of Nrf2 in Oxidative Stress, Neuroinflammation and Autophagy in Alzheimer’s Disease: Regulation of Nrf2 by Different Signaling Pathways
Current Molecular Medicine 25, 372 (2025); https://doi.org/10.2174/1566524023666230726145447
/content/journals/cmm/10.2174/1566524023666230726145447
/content/journals/cmm/10.2174/1566524023666230726145447
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  • Article Type:     Review Article
Keyword(s): GSK-3; HO-1; NF-κB; p38MAPK; PI3K; ROS

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