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<p>Alzheimer’s disease (AD), a leading cause of dementia, remains incurable, necessitating novel insights into its pathogenesis and therapeutic strategies. Recent studies highlight cuproptosis—a copper (Cu)-dependent mitochondrial cell death pathway—as a critical player in AD progression. Cuproptosis is triggered by Cu overload, which disrupts mitochondrial tricarboxylic acid cycle enzymes, resulting in toxic aggregation of lipoylated proteins and iron-sulfur cluster destabilization. This process exacerbates mitochondrial dysfunction, oxidative stress, and neuronal loss, synergizing with hallmark AD pathologies like Aβ deposition and Tau hyperphosphorylation. Unlike ferroptosis or apoptosis, cuproptosis uniquely involves mitochondrial protein lipoylation and Cu homeostasis imbalance. Therapeutic strategies targeting cuproptosis include Cu chelators, inhibitors of Cu transporters, antioxidants, and gene editing approaches to restore Cu homeostasis or mitigate protein aggregation. Immunotherapy and neuroprotective agents further show promise in alleviating cuproptosis-driven neuroinflammation. Despite preclinical advancements, challenges remain in balancing Cu’s essential roles with therapeutic interventions. This review underscores cuproptosis as a pivotal mechanism in AD and outlines emerging therapeutic avenues, emphasizing the ncessity for precision in targeting Cu dysregulation to halt neurodegeneration.</p>

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Unveiling the pathogenesis and therapeutic strategies of Alzheimer’s disease through cuproptosis

  • 期刊论文

  • 发表日期：

    2026年6月18日

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  • Shuangfeng Xu,
  • Jing Mu,
  • Zhifeng Wang,
  • Jiao Yang,
  • Daman Tian,
  • Ting Shi,
  • Junfeng Lan,
  • Pengfen He,
  • Zhihui Hao,
  • Youchuan Fu,
  • Liwei Xing,
  • Jianzhou Ye,
  • Jian Wang

摘要

Alzheimer’s disease (AD), a leading cause of dementia, remains incurable, necessitating novel insights into its pathogenesis and therapeutic strategies. Recent studies highlight cuproptosis—a copper (Cu)-dependent mitochondrial cell death pathway—as a critical player in AD progression. Cuproptosis is triggered by Cu overload, which disrupts mitochondrial tricarboxylic acid cycle enzymes, resulting in toxic aggregation of lipoylated proteins and iron-sulfur cluster destabilization. This process exacerbates mitochondrial dysfunction, oxidative stress, and neuronal loss, synergizing with hallmark AD pathologies like Aβ deposition and Tau hyperphosphorylation. Unlike ferroptosis or apoptosis, cuproptosis uniquely involves mitochondrial protein lipoylation and Cu homeostasis imbalance. Therapeutic strategies targeting cuproptosis include Cu chelators, inhibitors of Cu transporters, antioxidants, and gene editing approaches to restore Cu homeostasis or mitigate protein aggregation. Immunotherapy and neuroprotective agents further show promise in alleviating cuproptosis-driven neuroinflammation. Despite preclinical advancements, challenges remain in balancing Cu’s essential roles with therapeutic interventions. This review underscores cuproptosis as a pivotal mechanism in AD and outlines emerging therapeutic avenues, emphasizing the ncessity for precision in targeting Cu dysregulation to halt neurodegeneration.