S100A8 knockdown activates the PI3K/AKT signaling pathway to inhibit microglial autophagy and improve cognitive impairment mediated by chronic sleep deprivation

作者：Yanhong Xiong, Weidong Liang, Xifeng Wang, Hong‐Jian Zhu, Pengcheng Yi, Gen Wei, Hailin Liu, Yue Lin, Lieliang Zhang, Jun Ying, Fuzhou Hua · 发表于：International Immunopharmacology · 年份：2024 · DOI：10.1016/j.intimp.2024.113375 · 被引用次数：16 · 研究领域：S100 Proteins and Annexins、Autophagy in Disease and Therapy、Sleep and related disorders

OBJECTIVE: Cognitive dysfunction is one of the major symptoms of chronic sleep deprivation (CSD). Abnormal autophagy and apoptosis are thought to be important mechanisms. S100 Calcium Binding Protein A8 (S100A8) plays a key role in autophagy and apoptosis of microglia. This study investigated whether S100A8 knockdown can effectively inhibit aberrant autophagy in microglia and improve cognitive function by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway under CSD conditions. METHODS: CSD mouse models and BV2 cell autophagy models were established in vivo and in vitro. Transcriptome sequencing was used to determine the key regulator related to autophagy. The Morris water maze test was used to evaluate the cognitive behavior of the mice. RT-qPCR and western blot were conducted to examine S100A8 expression and autophagy signalling. HE, TUNEL, transmission electron microscopy, immunofluorescence, and histochemistry were performed to detect pathological changes, neuronal autophagy, apoptosis, or positive cells in hippocampal tissues, respectively. RESULTS: Transcriptome sequencing showed that S100A8 was significantly elevated in CSD mice, and fluorescence colocalization results further suggested that S100A8 mainly colocalizes with microglia. In vivo studies revealed that knockdown of S100A8 alleviated CSD-induced cognitive impairment in mice. Through further mechanistic investigations employing both in vivo and in vitro models, we demons...