Journal Article

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

Lv, Renjun, Zhang, Zongyong, Xu, Song, Wang, Xinyu, Lu, Lin, Lu, Tangsheng, Yin, Qingqing, Jiang, Ziying, Liu, Xiaoxing, Liu, Bin, Wang, Yifei, Gao, Zhenfang, Li, Shangbin, Yuan, Kai, Zhu, Mengna, Wang, Xinning, Zhao, Peiqing, Hao, Junwei

2025

Overview

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. Diabetes-associated cognitive dysfunction (DACD) is increasingly recognized as a critical complication of diabetes. Here, the authors show that SGK1 drives hippocampal demyelination and DACD via regulating NDRG1 phosphorylation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/2 / 13/51 / 14/28 / 38/32 / 38/91 / 631/378/1689/132 / 631/378/2583 / 64/110 / 64/60 / 692/163/2743/137/138 / 96/31 / 96/63 / Animals / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cognitive Dysfunction - etiology / Cognitive Dysfunction - genetics / Cognitive Dysfunction - metabolism / Cognitive Dysfunction - pathology / Demyelinating Diseases - genetics / Demyelinating Diseases - metabolism / Demyelinating Diseases - pathology / Demyelination / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - complications / Diabetes Mellitus, Experimental - genetics / Diabetes Mellitus, Experimental - metabolism / Disease Models, Animal / Gene sequencing / Glucocorticoids / Hippocampus / Hippocampus - metabolism / Hippocampus - pathology / Humanities and Social Sciences / Immediate-Early Proteins - genetics / Immediate-Early Proteins - metabolism / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Male / Males / Mice / Mice, Inbred C57BL / multidisciplinary / Myc protein / Myelin Sheath - metabolism / Myelination / Oligodendrocytes / Oligodendroglia - metabolism / Oligodendroglia - pathology / Phosphorylation / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Science / Science (multidisciplinary) / snRNA