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Background <p>Chronic kidney disease (CKD) is increasingly associated with cognitive impairment, yet the molecular pathways connecting systemic inflammation to synaptic dysfunction remain unclear. This study investigates the role of the Ccl4-Ccr5 axis in microglia-mediated synaptic phagocytosis during CKD-associated cognitive decline.</p> Methods <p>A 5/6 nephrectomy rat model was established in rats to induce CKD, validated by renal function markers. Cognitive performance was evaluated through spatial, contextual, and recognition memory tests. Hippocampal cellular alterations were analyzed using single-cell RNA sequencing and immunofluorescence for microglial activation and synaptic density. The functional roles of <i>Ccr5</i> were assessed via in vivo and in vitro CRISPR-mediated knockdown or overexpression, while Ccl4-Ccr5 interactions were confirmed by co-immunoprecipitation.</p> Results <p>CKD rats showed significant cognitive deficits, increased hippocampal microgliosis, and synaptic loss. <i>Ccr5</i> knockdown reduced microglial synaptic engulfment, restored synaptic plasticity, and improved memory, whereas <i>Ccr5</i> overexpression enhanced phagocytic activity.</p> Conclusions <p>These findings demonstrate that Ccl4-Ccr5 signaling drives pathological synaptic elimination by microglia, linking systemic inflammation to cognitive decline in CKD. Targeting this pathway may provide a therapeutic approach to preserve neuronal function.</p>

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Microglial Ccl4-Ccr5 signaling links systemic inflammation to synaptic loss and memory deficits in chronic kidney disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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  • Yaochen Cao,
  • Jingyun Wang,
  • Xitong Li,
  • Xin Chen,
  • Jinsheng Xiong,
  • Tianyao Wang,
  • Hongming Sun,
  • Ziqiang Wang

摘要

Background

Chronic kidney disease (CKD) is increasingly associated with cognitive impairment, yet the molecular pathways connecting systemic inflammation to synaptic dysfunction remain unclear. This study investigates the role of the Ccl4-Ccr5 axis in microglia-mediated synaptic phagocytosis during CKD-associated cognitive decline.

Methods

A 5/6 nephrectomy rat model was established in rats to induce CKD, validated by renal function markers. Cognitive performance was evaluated through spatial, contextual, and recognition memory tests. Hippocampal cellular alterations were analyzed using single-cell RNA sequencing and immunofluorescence for microglial activation and synaptic density. The functional roles of Ccr5 were assessed via in vivo and in vitro CRISPR-mediated knockdown or overexpression, while Ccl4-Ccr5 interactions were confirmed by co-immunoprecipitation.

Results

CKD rats showed significant cognitive deficits, increased hippocampal microgliosis, and synaptic loss. Ccr5 knockdown reduced microglial synaptic engulfment, restored synaptic plasticity, and improved memory, whereas Ccr5 overexpression enhanced phagocytic activity.

Conclusions

These findings demonstrate that Ccl4-Ccr5 signaling drives pathological synaptic elimination by microglia, linking systemic inflammation to cognitive decline in CKD. Targeting this pathway may provide a therapeutic approach to preserve neuronal function.