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

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.