Striking a NRF2: The Rusty and Rancid Vulnerabilities Toward Ferroptosis in Alzheimer's Disease.

Significance: The lack of disease-modifying treatments for Alzheimer's disease (AD) that substantially alter the course of the disease highlights the need for new biological models of disease progression and neurodegeneration. Oxidation of macromolecules within the brain, including lipids, proteins, and DNA, is believed to contribute to AD pathophysiology, concomitant with dysregulation of redox-active metals, such as iron. Creating a unified model of pathogenesis and progression underpinned by iron dysregulation and redox dysregulation in AD could lead to new therapeutic targets with disease-modifying potential. Recent Advances: Ferroptosis, which was named in 2012, is a necrotic form of regulated cell death that depends on both iron and lipid peroxidation. While it is distinct from other types of regulated cell death, ferroptosis is regarded as being mechanistically synonymous with oxytosis. The ferroptosis paradigm has great explanatory potential in describing how neurons degenerate and die in AD. At the molecular level, ferroptosis is executed by the lethal accumulation of phospholipid hydroperoxides generated by the iron-dependent peroxidation of polyunsaturated fatty acids, while the major defensive protein against ferroptosis is the selenoenzyme, glutathione peroxidase 4 (GPX4). An expanding network of protective proteins and pathways have also been identified to complement GPX4 in the protection of cells against ferroptosis, with a central role emerging for nuclear factor erythroid 2-related factor 2 (NRF2). Critical Issues: In this review, we provide a critical overview of the utility of ferroptosis and NRF2 dysfunction in understanding the iron- and lipid peroxide-associated neurodegeneration of AD. Future Directions: Finally, we discuss how the ferroptosis paradigm in AD is providing a new spectrum of therapeutic targets. Antioxid. Redox Signal. 39, 141-161.

Ferroptosis and NRF2: an emerging battlefield in the neurodegeneration of Alzheimer's disease.

Ferroptosis is an iron- and lipid peroxidation-dependent cell death modality and emerging evidence indicates that ferroptosis has great explanatory potential for neuronal loss and associated CNS dysfunction in a range of neurodegenerative diseases (e.g., Alzheimer's, Parkinson's and Huntington's diseases, Motor neuron disease, Friedreich ataxia (FRDA)). Ferroptotic death results from lethal levels of phospholipid hydroperoxides that are generated by iron-dependent peroxidation of polyunsaturated fatty acids (PUFAs), such as arachidonic and adrenic acids, which are conjugated to specific phospholipids (e.g., phosphatidylethanolamines (PEs)). The major cellular protector against ferroptosis is glutathione peroxidase 4 (GPX4), a membrane-associated selenoenzyme that reduces deleterious phospholipid hydroperoxides to their corresponding benign phospholipid alcohols in a glutathione-dependent manner. Other complementary protective systems have also been identified that act to bolster cellular defences against ferroptosis. Many pharmacological modulators of the ferroptosis pathway have been identified, targeting proteins involved in iron homoeostasis and autophagy; the production and detoxification of lipid peroxides, and cyst(e)ine/glutathione metabolism. While a growing number of cell signalling pathways converge to regulate the ferroptosis cascade, an emerging understanding of ferroptosis regulation suggests that the ferroptotic 'tone' of cells can be set by the transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), which transcriptionally controls many key components of the ferroptosis pathway. In this review, we provide a critical overview of the relationship between ferroptosis and NRF2 signalling. With a focus on the role of ferroptosis in Alzheimer's disease (AD), we discuss how therapeutic modulation of the NRF2 pathway is a viable strategy to explore in the treatment of ferroptosis-driven neurodegeneration.