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<p>Alzheimer’s disease (AD) is characterized by the accumulation of neurofibrillary tangles (NFTs) composed of misfolded tau and by early mitochondrial dysfunction. Although tau aggregation has been closely linked to mitochondrial impairment and neuronal toxicity, the molecular factors that amplify tau-induced mitochondrial damage remain incompletely understood. Previous studies have shown that cofilin-1, an actin-binding protein, facilitates tau aggregation and propagation under pathological conditions. In the present study, using tauopathy-based cellular models, we investigated whether cofilin-1 modulates tau-induced mitochondrial dysfunction. We found that tau aggregates and cofilin-1 exhibit spatial proximity to mitochondria as assessed by fluorescence microscopy, and that the presence of cofilin-1 markedly exacerbates tau-induced mitochondrial structural abnormalities, impaired fusion dynamics, oxidative stress, and activation of intrinsic apoptotic signaling. Importantly, these effects were consistently more pronounced in cells treated with tau/cofilin-1 composite fibrils compared with tau fibrils alone. Together, our findings indicate that cofilin-1 functions as a critical amplifier of tau-mediated mitochondrial toxicity under pathological conditions. Rather than demonstrating a direct physical interaction, this study supports a model in which cofilin-1 synergistically enhances tau-induced mitochondrial dysfunction, oxidative stress, and cell death, thereby contributing to tau-driven neurodegenerative processes relevant to AD.</p>

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Cofilin-1 Exacerbates Tau-Induced Mitochondrial Damage, Oxidative Stress, and Apoptosis in Alzheimer’s Disease

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • Yidan Chen,
  • Di Zhang,
  • Qian Zhang,
  • Qin Li,
  • Dan Yan,
  • Hualan Qin,
  • Ying Xiong,
  • Chuhang Zhang,
  • Yue Wan,
  • Mingmin Yan

摘要

Alzheimer’s disease (AD) is characterized by the accumulation of neurofibrillary tangles (NFTs) composed of misfolded tau and by early mitochondrial dysfunction. Although tau aggregation has been closely linked to mitochondrial impairment and neuronal toxicity, the molecular factors that amplify tau-induced mitochondrial damage remain incompletely understood. Previous studies have shown that cofilin-1, an actin-binding protein, facilitates tau aggregation and propagation under pathological conditions. In the present study, using tauopathy-based cellular models, we investigated whether cofilin-1 modulates tau-induced mitochondrial dysfunction. We found that tau aggregates and cofilin-1 exhibit spatial proximity to mitochondria as assessed by fluorescence microscopy, and that the presence of cofilin-1 markedly exacerbates tau-induced mitochondrial structural abnormalities, impaired fusion dynamics, oxidative stress, and activation of intrinsic apoptotic signaling. Importantly, these effects were consistently more pronounced in cells treated with tau/cofilin-1 composite fibrils compared with tau fibrils alone. Together, our findings indicate that cofilin-1 functions as a critical amplifier of tau-mediated mitochondrial toxicity under pathological conditions. Rather than demonstrating a direct physical interaction, this study supports a model in which cofilin-1 synergistically enhances tau-induced mitochondrial dysfunction, oxidative stress, and cell death, thereby contributing to tau-driven neurodegenerative processes relevant to AD.