Natural antioxidants that act against Alzheimer's disease through modulation of the NRF2 pathway: a focus on their molecular mechanisms of action

Abstract

Characterized by a complex pathophysiology that includes the intraneuronal formation of neurofibrillary tangles and the extracellular deposition of β-amyloid plaques, Alzheimer's disease (AD) is a terminal neurodegenerative disease that causes dementia in older adults. Oxidative stress in the brain is considered as one of the contributing factors to the pathogenesis of AD, and thus, antioxidants have attracted much interest as potential therapeutic agents against the disorder. Natural antioxidants are typically characterized by low acute and chronic toxicity, which facilitates their potential therapeutic application. One important molecular target for the beneficial effects of natural antioxidants is the nuclear factor erythroid-derived 2-related factor 2 (NFE2L2/NRF2). NRF2 is a key transcription factor that orchestrates the cellular antioxidant response through regulating the expression of oxidative stress-related genes harboring the antioxidant response element (ARE) in their promoters. Indeed, in the case of excessive oxidative damage, NRF2 migrates to the nucleus and binds to ARE, activating the transcription of antioxidant protector genes. There is increasing evidence that NRF2 is implicated in AD pathology through dysfunction and altered localization, which renders it as a potential therapeutic target for AD. Thus, this review summarizes the most recent (2018-2023) advances on the NRF2-modulating activity of natural antioxidants observed in vitro and in AD animal models. This information will help elucidate the molecular mechanisms governing the antioxidant activity of such phytochemicals to highlight their therapeutic potential against common neurodegenerative diseases, such as AD.

Keywords: Alzheimer’s disease; NRF2; antioxidants; neurodegenerative diseases; neuroprotection; oxidative stress; reactive oxygen species.

Figure 1

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. The underlying pathological changes in the brain of individuals with AD include the following key features: Amyloid plaques: Extracellular deposits of beta-amyloid protein (Aβ) form amyloid plaques. These plaques are composed of aggregated Aβ peptides derived from the cleavage of the amyloid precursor protein (APP). Neurofibrillary tangles: Intracellular neurofibrillary tangles are formed by the hyperphosphorylation and aggregation of tau protein. In healthy neurons, tau helps maintain the structural integrity of microtubules, but in AD, abnormal tau protein forms twisted filaments, leading to the formation of tangles. Neuronal loss: AD is associated with significant neuronal loss, particularly in brain regions involved in memory and cognitive functions, such as the hippocampus and neocortex. Neuronal loss contributes to the progressive decline in cognitive abilities. Synaptic dysfunction: Synaptic loss and dysfunction occur early. Disruptions in the communication between neurons impair memory formation and retrieval. Synaptic loss is believed to be caused by the accumulation of Aβ and tau pathology. Inflammatory response: AD is characterized by chronic neuroinflammation. Activated microglia and astrocytes are observed in affected brain regions, releasing pro-inflammatory molecules that contribute to neuronal damage. Oxidative stress: The increased production of free radicals and ROS, along with the overexpression of prooxidant enzymes and the dysfunction of mitochondria, contribute to chronic oxidative stress observed in the brain, that is intertwined with chronic neuroinflammation. Vascular changes: Vascular abnormalities are frequently observed in AD. Cerebral blood flow alterations, blood-brain barrier dysfunction, and the accumulation of vascular deposits, known as cerebral amyloid angiopathy, are seen in affected individuals.

Figure 2

The mechanism of action of nuclear factor erythroid-derived 2-related factor 2 (NRF2) in basal and oxidative stress conditions. (A) Under basal conditions, NRF2 is sequestered by Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm leading to its ubiquitination and subsequent proteasomal degradation. Glycogen synthase kinase-3β (GSK-3β) phosphorylates NRF2 leading again to the proteasomal degradation of NRF2. The PI3K (phosphoinositide-3 kinase)/Akt (protein kinase B) signaling pathway phosphorylates GSK-3β at serine 9 to keep it in an inactive state, thereby protecting NRF2 from proteasomal degradation. (B) Under oxidative stress conditions, NRF2 is released from Keap1 and is translocated to the nucleus where it dimerizes with small musculoaponeurotic fibrosarcoma proteins (sMafs) and binds to specific DNA regions, the antioxidant response element (ARE) sequences. This regulates the expression of antioxidant genes, such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (GPx), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase regulatory subunit (GCLM). It also downregulates the expression of pro-oxidant and pro-inflammatory genes, such as nitric oxide synthase 2 (NOS2), interleukin (IL)-6, cyclooxygenase 2 (COX-2), nuclear factor kappa beta (NF-κB), and tumor necrosis factor-a (TNF-a). 5’-Adenosine monophosphate-activated protein kinase (AMPK) is also linked to the phosphorylation and direct activation of NRF2 nuclear translocation, tuning the transactivation of antioxidant genes. ROS, reactive oxygen species; Ub, ubiquitin.

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.

Figure 4

The restoration of the pathway of nuclear factor erythroid-derived 2-related factor 2 (NRF2) in Alzheimer’s disease (AD) models that are treated with phytochemicals. Phytochemicals scavenge reactive oxygen species (ROS) and free radicals reducing oxidative stress in the brain. They also upregulate NRF2, restoring its nuclear translocation that is inhibited in AD, thus upregulating antioxidant genes and downregulating pro-oxidant and pro-inflammatory genes. GSK-3β (glycogen synthase kinase-3β) has also been shown to be inhibited by certain phytochemicals, reducing the phosphorylation and subsequent aggregation of tau protein, along with the other AD pathological findings. Aβ, amyloid beta; Keap1, Kelch-like ECH-associated protein 1; 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; NFTs, neurofibrillary tangles.