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<p>Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with circadian rhythm disturbances strongly linked to its pathogenesis. The choroid plexus (ChP) is a circadian-regulated structure in the brain ventricles, but the role of the core clock gene brain and muscle ARNT-like protein 1 (<i>BMAL1</i>) in ChP in relation to AD pathology remains unclear. Here, we report that knockdown of <i>Bmal1</i> in ChP epithelial cells of 5xFAD mice alleviates amyloid-β (Aβ) pathology, primarily by improving the function of astrocytes and border-associated macrophages (BAMs), with the latter potentially mediated by the upregulation of the secreted protein glutathione peroxidase 3 (GPX3), which reduces lipid peroxidation in BAMs. Collectively, our findings establish the ChP-driven BMAL1-GPX3 axis as a new Aβ clearance mechanism, with GPX3 representing a promising therapeutic target. These findings provide new mechanistic insights into AD and suggest innovative treatment approaches.</p>

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BMAL1-GPX3 axis in the choroid plexus mitigates Aβ pathology in an amyloid mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Fenglin Tang,
  • Yufeng Li,
  • Xue Bai,
  • Zhongmou Zhu,
  • Hongwei Dong,
  • Jianhui Chen,
  • Bo Ye,
  • Meng Yuan,
  • Qilong Wu,
  • Weishan Fu,
  • Yuan Zhang,
  • Chao Wang

摘要

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with circadian rhythm disturbances strongly linked to its pathogenesis. The choroid plexus (ChP) is a circadian-regulated structure in the brain ventricles, but the role of the core clock gene brain and muscle ARNT-like protein 1 (BMAL1) in ChP in relation to AD pathology remains unclear. Here, we report that knockdown of Bmal1 in ChP epithelial cells of 5xFAD mice alleviates amyloid-β (Aβ) pathology, primarily by improving the function of astrocytes and border-associated macrophages (BAMs), with the latter potentially mediated by the upregulation of the secreted protein glutathione peroxidase 3 (GPX3), which reduces lipid peroxidation in BAMs. Collectively, our findings establish the ChP-driven BMAL1-GPX3 axis as a new Aβ clearance mechanism, with GPX3 representing a promising therapeutic target. These findings provide new mechanistic insights into AD and suggest innovative treatment approaches.