Cuproptosis: mechanisms and links with Alzheimer’s disease

作者：Nan Zheng, Qiong Zhou, Zihao Chen, Lihua Xie, Xinyu Yang, Ziwen Chen, Fuwei Wang, Qiang Sun, Jikun Du, Jiantao Lin, Li Li, Baohong Li · 发表于：Journal of Neurophysiology · 年份：2025 · DOI：10.1152/jn.00370.2025 · 被引用次数：7 · 研究领域：Mitochondrial Function and Pathology

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 chel...