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

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 Lu () and Qingqing Yin ()
Additional contact information
Ziying Jiang: Capital Medical University
Bin Liu: Shandong Institute of Neuroimmunology
Tangsheng Lu: Peking University
Xiaoxing Liu: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Renjun Lv: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Kai Yuan: National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital)
Mengna Zhu: Shandong First Medical University & Shandong Academy of Medical Sciences
Xinning Wang: Shandong First Medical University & Shandong Academy of Medical Sciences
Shangbin Li: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Song Xu: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Xinyu Wang: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Yifei Wang: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Zhenfang Gao: Shandong First Medical University & Shandong Academy of Medical Sciences
Peiqing Zhao: Zibo Central Hospital Affiliated to Binzhou Medical University
Zongyong Zhang: Shandong First Medical University & Shandong Academy of Medical Sciences
Junwei Hao: Capital Medical University
Lin Lu: Peking University
Qingqing Yin: Shandong Provincial Hospital Affiliated to Shandong First Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-56854-2

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