Notch/NF-κB 交互信号控制脑衰老中的 SASP 基因表达
Notch/NF-κB crosstalk signaling controls SASP gene expression during brain aging
研究在多种转基因小鼠模型中显示，脑衰老广泛伴随 NF-κB 激活与 Notch 信号受抑。在年轻小鼠星形胶质细胞中激活 NF-κB 可模拟早发的 SASP 形成，同时抑制 Notch 信号。生物信息学分析在体内鉴定出 SASP 基因内由 Notch/RBPJ 与 NF-κB 转录因子共同占据的保守交互位点，使两类因子能够组合调控。激活的 Notch 可通过选择性物理互作在多个分子层面负向调节 NF-κB 信号；在体外原代星形胶质细胞中药理激活 Notch 显著降低 NF-κB 驱动的 SASP 基因表达。作者据此提出 Notch–NF-κB 交互可作为缓解脑部炎性衰老的潜在治疗靶点。
来源：Nucleic Acids Research · doi.org
Brain aging is associated with chronic, low-grade inflammation known as inflammaging, which is largely driven by senescent glial cells secreting pro-inflammatory factors termed as senescence-associated secretory phenotype (SASP). In humans, the release of SASP factors in the brain is linked with an increased risk for the development of neurodegenerative disorders; thus, elucidating the underlying molecular mechanisms is essential for understanding the pathophysiology of brain aging. Both NF-κB and Notch signaling are known to regulate SASP expression; however, their mode of interaction in brain inflammaging is poorly understood. Here, we demonstrate that brain aging is broadly associated with NF-κB activation but Notch suppression using different transgenic mouse models. Astrocytic NF-κB activation in young mice was able to mimic premature SASP formation but repressed Notch signaling in parallel. Bioinformatic analyses further identified conserved crosstalk sites within SASP genes co-occupied by Notch/RBPJ and NF-κB transcription factors in vivo, allowing specific combinatorial regulation. Importantly, selective physical interactions enable that activated Notch can act as a negative modulator of NF-κB signaling at different molecular levels. Consistently, pharmacological activation of Notch in primary astrocytes significantly reduced NF-κB-driven SASP gene expression. Together, these findings identify Notch–NF-κB crosstalk as a potential therapeutic target to mitigate brain inflammaging.