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. 2023 Jul 3;14:1217730. doi: 10.3389/fendo.2023.1217730

Figure 3.

Figure 3

The impaired pathway of nuclear factor erythroid-derived 2-related factor 2 (NRF2) in Alzheimer’s disease (AD) patients. This pathway is dysregulated in AD, where oxidative stress in the brain positively regulates NRF2, but its nuclear translocation is inhibited, therefore there is decreased expression of antioxidant genes and overexpression of pro-oxidant and pro-inflammatory genes. Beta-amyloid (Aβ) plaques enhance oxidative stress, reduce NRF2 and inhibit its dissociation from Keap1 (Kelch-like ECH-associated protein 1). This altered regulation of NRF2 in the brains of AD patients leads to the accumulation of misfolded proteins, including the accumulation of Aβ and neurofibrillary tangles (NFTs), the hyperphosphorylation of tau, which is also carried out by GSK-3β (glycogen synthase kinase-3β), and its subsequent aggregation, further exacerbating oxidative stress and neuroinflammation. ROS, reactive oxygen species; sMafs, small musculoaponeurotic fibrosarcoma proteins; ARE, antioxidant response element; HO-1, heme oxygenase-1; NQO1, NAD(P)H quinone oxidoreductase 1; GPx, glutathione peroxidase; GCLC, glutamate-cysteine ligase catalytic subunit; GCLM, glutamate-cysteine ligase regulatory subunit; NOS2, nitric oxide synthase 2; IL-6, interleukin-6; COX-2, cyclooxygenase 2; NF-κB, nuclear factor kappa beta; TNF-a, tumor necrosis factor-a.