Work

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

Year: 2025

Type: article

Abstract: 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.

Source: Journal of Neuroinflammation

DOI: 10.1186/s12974-025-03633-x