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<p>Although systemic inflammation has been implicated in PD pathogenesis, the underlying mechanisms remain poorly understood. In this study, we investigate the pathological events in a systemic inflammation-induced PD mouse model. We demonstrate that synaptic loss in the midbrain occurs as early as 1 day after the final lipopolysaccharide (LPS) administration, preceding dopaminergic (DA) neuron degeneration, which was observed only at later stages (14 days). Early microglial activation in the midbrain is detected, accompanied by excessive synaptic engulfment, suggesting a critical role of microglia-dependent synapse elimination in PD pathogenesis. Furthermore, we identify the complement receptor 3 (CR3) as a key mediator of microglial synaptic engulfment, revealing that its inhibition rescues synaptic integrity and prevents neurodegeneration. Our results contribute to a deeper understanding of early events of PD progression driven by systemic inflammation and provide early intervention strategies targeting microglial complement signaling to halt PD progression.</p>

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Complement receptor 3 (CR3)-dependent microglial synapse elimination drives Parkinson’s disease pathogenesis in systemic inflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Lei Cai,
  • Yihe Zhang,
  • Jiayi Li,
  • Lamei Hu,
  • Qinghao Meng,
  • Jingyi Shao,
  • Haotian Deng,
  • Yiying Liu,
  • Jiaqi Liu,
  • Yue Liang,
  • Nanshan Song,
  • Jianhua Ding,
  • Yi Fan,
  • Ming Lu,
  • Yinquan Fang,
  • Gang Hu

摘要

Although systemic inflammation has been implicated in PD pathogenesis, the underlying mechanisms remain poorly understood. In this study, we investigate the pathological events in a systemic inflammation-induced PD mouse model. We demonstrate that synaptic loss in the midbrain occurs as early as 1 day after the final lipopolysaccharide (LPS) administration, preceding dopaminergic (DA) neuron degeneration, which was observed only at later stages (14 days). Early microglial activation in the midbrain is detected, accompanied by excessive synaptic engulfment, suggesting a critical role of microglia-dependent synapse elimination in PD pathogenesis. Furthermore, we identify the complement receptor 3 (CR3) as a key mediator of microglial synaptic engulfment, revealing that its inhibition rescues synaptic integrity and prevents neurodegeneration. Our results contribute to a deeper understanding of early events of PD progression driven by systemic inflammation and provide early intervention strategies targeting microglial complement signaling to halt PD progression.