Ferroptosis and cognitive impairment: Unraveling the link and potential therapeutic targets

Abstract

Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, share key characteristics, notably cognitive impairment and significant cell death in specific brain regions. Cognition, a complex mental process allowing individuals to perceive time and place, is disrupted in these conditions. This consistent disruption suggests the possibility of a shared underlying mechanism across all neurodegenerative diseases. One potential common factor is the activation of pathways leading to cell death. Despite significant progress in understanding cell death pathways, no definitive treatments have emerged. This has shifted focus towards less-explored mechanisms like ferroptosis, which holds potential due to its involvement in oxidative stress and iron metabolism. Unlike apoptosis or necrosis, ferroptosis offers a novel therapeutic avenue due to its distinct biochemical and genetic underpinnings, making it a promising target in neurodegenerative disease treatment. Ferroptosis is distinguished from other cellular death mechanisms, by distinctive characteristics such as an imbalance of iron hemostasis, peroxidation of lipids in the plasma membrane, and dysregulated glutathione metabolism. In this review, we discuss the potential role of ferroptosis in cognitive impairment. We then summarize the evidence linking ferroptosis biomarkers to cognitive impairment brought on by neurodegeneration while highlighting recent advancements in our understanding of the molecular and genetic mechanisms behind the condition. Finally, we discuss the prospective therapeutic implications of targeting ferroptosis for the treatment of cognitive abnormalities associated with neurodegeneration, including natural and synthetic substances that suppress ferroptosis via a variety of mechanisms. Promising therapeutic candidates, including antioxidants and iron chelators, are being explored to inhibit ferroptosis and mitigate cognitive decline.

Keywords: Cell death; Cognitive impairments; Ferroptosis; Neurodegeneration; Neurotherapeutics.