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<p>Disruptions in the glymphatic system and its downstream meningeal lymphatic drainage pathway, crucial for brain waste clearance, are linked to the pathogenesis of Alzheimer’s disease (AD), yet the underlying mechanisms remain unclear. Abnormal calcium dynamics in astrocytes represents an early event in the mouse models of AD. Here we show functional association between amyloid-β-induced elevation of Ca<sup>2+</sup> dynamics in medial prefrontal cortex astrocytes and glymphatic dysfunction in cognitively impaired 5xFAD mice, which can be alleviated by the attenuation of G<sub>q</sub> GPCR-evoked Ca<sup>2+</sup> activity. Mechanistically, Ca<sup>2+</sup> hyperactivity increases cholesterol synthesis in astrocytes, leading to increased aquaporin-4 (AQP4) endocytosis and relocalization to lysosomes, thereby disrupting AQP4 polarity and glymphatic function. Suppressing cholesterol synthesis by either specifically knocking down squalene epoxidase in astrocytes or atorvastatin administration improves glymphatic perfusion, meningeal lymphatic drainage and cognition performance in 5xFAD mice. Our data reveal potential therapeutic benefits of lowering astrocyte calcium activity and cholesterol synthesis for enhancing glymphatic–lymphatic coupling integrity in the early stages of AD pathogenesis.</p>

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Amyloid-β-driven glymphatic dysfunction in Alzheimer’s disease model mice is driven by Ca2+-mediated increases in astrocytic cholesterol

  • 期刊论文

  • 发表日期：

    2026年4月15日

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  • Zhan Zhang,
  • Shaojian Li,
  • Liang Xu,
  • Songhua Xiao,
  • Yi Li,
  • Jialin Huang,
  • Jingxuan Huang,
  • You Zuo,
  • Wenjie Wen,
  • Qingyuan Dai,
  • Chuan Xiao,
  • Xinkai Zhang,
  • Jiongxue Chen,
  • Fuyin Deng,
  • Jinbiao Li,
  • Yongteng Xu,
  • Xia Hu,
  • Zhenhong Deng,
  • Yuan Luo,
  • Xiaoru Xie,
  • Xiaojing Ye,
  • Wei-Jye Lin,
  • Yamei Tang

摘要

Disruptions in the glymphatic system and its downstream meningeal lymphatic drainage pathway, crucial for brain waste clearance, are linked to the pathogenesis of Alzheimer’s disease (AD), yet the underlying mechanisms remain unclear. Abnormal calcium dynamics in astrocytes represents an early event in the mouse models of AD. Here we show functional association between amyloid-β-induced elevation of Ca2+ dynamics in medial prefrontal cortex astrocytes and glymphatic dysfunction in cognitively impaired 5xFAD mice, which can be alleviated by the attenuation of Gq GPCR-evoked Ca2+ activity. Mechanistically, Ca2+ hyperactivity increases cholesterol synthesis in astrocytes, leading to increased aquaporin-4 (AQP4) endocytosis and relocalization to lysosomes, thereby disrupting AQP4 polarity and glymphatic function. Suppressing cholesterol synthesis by either specifically knocking down squalene epoxidase in astrocytes or atorvastatin administration improves glymphatic perfusion, meningeal lymphatic drainage and cognition performance in 5xFAD mice. Our data reveal potential therapeutic benefits of lowering astrocyte calcium activity and cholesterol synthesis for enhancing glymphatic–lymphatic coupling integrity in the early stages of AD pathogenesis.