SGK1 drives hippocampal demyelination and diabetes-associated cognitive dysfunction in mice

作者：Ziying Jiang, Bin Liu, Tangsheng Lu, Xiaoxing Liu, Renjun Lv, Kai Yuan, Mengna Zhu, Xinning Wang, Shangbin Li, Song Xu, Xinyu Wang, Yifei Wang, Zhenfang Gao, Peiqing Zhao, Zongyong Zhang, Junwei Hao, Lin Lü, Qingqing Yin · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-56854-2 · 被引用次数：11 · 研究领域：Alzheimer's disease research and treatments、Mechanisms of cancer metastasis、Neuroinflammation and Neurodegeneration Mechanisms

Diabetes-associated cognitive dysfunction (DACD) is increasingly recognized as a critical complication of diabetes. The complex pathology of DACD remains unknown. Here, we performed single-nucleus RNA sequencing (snRNA-seq) to demonstrate unique cellular and molecular patterns of the hippocampus from a mouse model of diabetes. More in-depth analysis of oligodendrocytes (OLs) distinguished five subclusters, indicating different functional states of OLs and transcriptional changes in each subcluster. Based on the results of snRNA-seq and experiments in vivo, we observed demyelination and disharmony of oligodendroglial lineage cell composition in male diabetic mice. Serum/glucocorticoid regulated kinase 1 (SGK1) expression was significantly increased in the hippocampus OLs of male diabetic mice, and SGK1 knockdown in hippocampus reversed demyelination and DACD via N-myc downstream-regulated gene 1 (NDRG1)-mediated pathway. The findings illustrated a transcriptional landscape of hippocampal OLs and substantiated impaired myelination in DACD. Our results provided direct evidence that inhibition of SGK1 or the promotion of myelination might be a potential therapeutic strategy for DACD.