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<p>Microglial functions are linked to Ca<sup>2+</sup> signaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer’s disease (AD), but how ER Ca<sup>2+</sup> receptors regulate microglial functions under physiological and AD conditions remains unclear. We found reduced ryanodine receptor 2 (<i>Ryr2</i>) expression in microglia from an AD mouse model. Modulation of RyR2 using S107, a RyR-Calstabin stabilizer, blunted spontaneous Ca<sup>2+</sup> transients in controls and normalized Ca<sup>2+</sup> transients in AD mice. S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia; however, these effects were absent in AD microglia. Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia, a mechanism impaired in AD. These results highlight the role of ER Ca<sup>2+</sup> receptors in both homeostatic and AD microglia, providing insights into microglial Ca<sup>2+</sup> malfunctions in AD.</p>

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Modulation of Ryanodine Receptors on Microglial Ramification, Migration, and Phagocytosis in an Alzheimer’s Disease Mouse Model

  • 期刊论文

  • 发表日期：

    2025年8月6日

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  • Yulin Ouyang,
  • Zihao Chen,
  • Qiang Huang,
  • Hai Zhang,
  • Haolin Song,
  • Xinnian Wang,
  • Wenxiu Dong,
  • Yong Tang,
  • Najeebullah Shah,
  • Shimin Shuai,
  • Yang Zhan

摘要

Microglial functions are linked to Ca2+ signaling, with endoplasmic reticulum (ER) calcium stores playing a crucial role. Microglial abnormality is a hallmark of Alzheimer’s disease (AD), but how ER Ca2+ receptors regulate microglial functions under physiological and AD conditions remains unclear. We found reduced ryanodine receptor 2 (Ryr2) expression in microglia from an AD mouse model. Modulation of RyR2 using S107, a RyR-Calstabin stabilizer, blunted spontaneous Ca2+ transients in controls and normalized Ca2+ transients in AD mice. S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia; however, these effects were absent in AD microglia. Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia, a mechanism impaired in AD. These results highlight the role of ER Ca2+ receptors in both homeostatic and AD microglia, providing insights into microglial Ca2+ malfunctions in AD.