Cuproptosis: mechanisms and links with Alzheimer's disease

Copper, an essential trace element in the human body, plays a crucial role in various metabolic processes, and its homeostasis imbalance is increasingly recognized as being associated with the pathology of Alzheimer's disease (AD). Notably, elevated levels of serum-free copper are linked to cognitive decline in patients with AD and may actively contribute to the disease process by promoting Aβ aggregation, tau protein hyperphosphorylation, and oxidative stress. A recent groundbreaking discovery identified a novel, copper-dependent form of regulated cell death-"cuproptosis"-characterized by lipoylated protein aggregation and loss of iron-sulfur clusters. This finding provides a new and compelling mechanistic link between copper overload and neuronal loss in AD. This article reviews the pathogenesis of cuproptosis, its relationship with copper homeostasis in the body, and its role in the pathogenesis of AD, including the regulatory functions of cuproptosis-related genes (CRGs) in AD. In addition, it explores potential therapeutic strategies aimed at correcting copper imbalance in AD, including the use of copper chelators, lipid peroxidation inhibitors, and antioxidants. These treatments aim to restore copper homeostasis and prevent cuproptosis in Alzheimer's disease. However, the clinical application of these strategies remains challenging due to issues such as poor bioavailability, significant side effects, and insufficient targeting. Therefore, developing an ideal copper chelator for clinical use remains a distant goal. Elucidating the role of cuproptosis in AD not only deepens our understanding of its pathogenesis but also opens innovative avenues for therapeutic intervention, representing a significant frontier in future AD research.