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<p>Traumatic brain injury (TBI) frequently causes cognitive dysfunction, with astrocytes playing a pivotal role in its pathogenesis. ​Specifically,​​ TBI triggers excessive astrocyte reactivity, ​leading to a phagocytic phenotype in astrocytes that contributes to abnormal synaptic phagocytosis and cognitive decline. ​Sirtuin 1 (SIRT1) reduction was region-specific, with significant downregulation observed in the hippocampus and cortex, reflecting the selective vulnerability of these regions to TBI-induced pathology. Although​ SIRT1 ​is​ a neuroprotective deacetylase, its regulatory mechanism in post-TBI astrocyte phagocytosis remains unclear. This study elucidates the mechanism through which SIRT1 attenuates TBI-induced cognitive deficits, specifically by ​​promoting autophagic flux in astrocytes​​ and subsequently ​​suppressing MEGF10-mediated synaptic phagocytosis​​. The investigation leveraged a combination of clinical human samples and astrocyte-specific murine models, including SIRT1-overexpression and ATG7-knockdown systems. Crucially, ​​astrocyte-specific knockdown of ATG7​​ was employed to mechanistically demonstrate that the SIRT1-driven degradation of MEGF10 and the consequent synaptic preservation are ​​strictly dependent on a functional autophagy pathway​​, as evidenced by the complete abolition of SIRT1’s beneficial effects upon ATG7 knockdown. ​Methodologies included​ Western blotting, immunofluorescence, behavioral tests (Barnes maze), and in vitro assays. Notably, TBI ​significantly​ reduced SIRT1 levels; astrocytic SIRT1 overexpression ​suppressed​ MEGF10 expression via ATG7-dependent autophagy, ​thereby​ alleviating astrogliosis, synaptic loss, and cognitive deficits. ​Critically, these protective effects were abrogated by​ ATG7 knockdown. ​Collectively, our results define​ the SIRT1-autophagy-MEGF10 axis ​as a key regulator​ of astrocytic phagocytosis, ​revealing​ a novel therapeutic target for injury-related cognitive dysfunction.</p>

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Astrocytic SIRT1 ameliorates cognitive deficits after traumatic brain injury via autophagy-mediated MEGF10 phagocytosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月30日

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  • Qianxin Ji,
  • Yan Zhang,
  • Zhuo Zhang,
  • Kun Cui,
  • Liang Zhao,
  • Xiaoyu Sun,
  • Huiling Qu,
  • Jia Song,
  • Jianru Xiao,
  • Xiaobin Zhang,
  • Yu Lu,
  • Jianan Xu,
  • Dan Li

摘要

Traumatic brain injury (TBI) frequently causes cognitive dysfunction, with astrocytes playing a pivotal role in its pathogenesis. ​Specifically,​​ TBI triggers excessive astrocyte reactivity, ​leading to a phagocytic phenotype in astrocytes that contributes to abnormal synaptic phagocytosis and cognitive decline. ​Sirtuin 1 (SIRT1) reduction was region-specific, with significant downregulation observed in the hippocampus and cortex, reflecting the selective vulnerability of these regions to TBI-induced pathology. Although​ SIRT1 ​is​ a neuroprotective deacetylase, its regulatory mechanism in post-TBI astrocyte phagocytosis remains unclear. This study elucidates the mechanism through which SIRT1 attenuates TBI-induced cognitive deficits, specifically by ​​promoting autophagic flux in astrocytes​​ and subsequently ​​suppressing MEGF10-mediated synaptic phagocytosis​​. The investigation leveraged a combination of clinical human samples and astrocyte-specific murine models, including SIRT1-overexpression and ATG7-knockdown systems. Crucially, ​​astrocyte-specific knockdown of ATG7​​ was employed to mechanistically demonstrate that the SIRT1-driven degradation of MEGF10 and the consequent synaptic preservation are ​​strictly dependent on a functional autophagy pathway​​, as evidenced by the complete abolition of SIRT1’s beneficial effects upon ATG7 knockdown. ​Methodologies included​ Western blotting, immunofluorescence, behavioral tests (Barnes maze), and in vitro assays. Notably, TBI ​significantly​ reduced SIRT1 levels; astrocytic SIRT1 overexpression ​suppressed​ MEGF10 expression via ATG7-dependent autophagy, ​thereby​ alleviating astrogliosis, synaptic loss, and cognitive deficits. ​Critically, these protective effects were abrogated by​ ATG7 knockdown. ​Collectively, our results define​ the SIRT1-autophagy-MEGF10 axis ​as a key regulator​ of astrocytic phagocytosis, ​revealing​ a novel therapeutic target for injury-related cognitive dysfunction.