2. Academic Validation
  3. OSBPL6 protects against demyelination and behavioral disorder via promoting cholesterol transport in oligodendrocyte

OSBPL6 protects against demyelination and behavioral disorder via promoting cholesterol transport in oligodendrocyte

  • J Adv Res. 2026 Jan 26:S2090-1232(26)00091-3. doi: 10.1016/j.jare.2026.01.066.
Mengni Chang 1,  Kaiqi Zhang 1,  Ye Li 1,  Xiao Chen 1,  Tian Lan 1,  Yan Zhu 1,  Wenjing Wang 1,  Changmin Wang 1,  Xianghua Zhuang 2,  Shihong Chen 3,  Shuyan Yu 4
Affiliations

Affiliations

  • 1 The Second Hospital of Shandong University, Jinan, Shandong Province 250012, China; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, China.
  • 2 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, Shandong Province 250033, China. Electronic address: [email protected].
  • 3 Department of Endocrinology and Metabolism, The Second Hospital of Shandong University, Jinan, Shandong Province 250033, China. Electronic address: [email protected].
  • 4 The Second Hospital of Shandong University, Jinan, Shandong Province 250012, China; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, China; Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province 250012, China. Electronic address: [email protected].
PMID: 41605285 DOI: 10.1016/j.jare.2026.01.066
Abstract

Introduction: Demyelination is associated with behavioral disorder and cognitive impairment in neuropsychiatric diseases, including major depressive disorder (MDD). However, the mechanism underlying myelin damage remains unclear, despite stress maybe a major risk factor.

Objectives: Here, we demonstrate that hippocampal neurons in the chronic stress-induced depressive mice are prone to demyelination due to disrupted Cholesterol transport to myelin sheaths in oligodendrocyte.

Methods and results: Single-nucleus RNA Sequencing of lipid metabolism-related signaling pathway revealed significant reduced levels of oxysterol binding protein-like 6 (OSBPL6) in hippocampal oligodendrocytes of depression mouse model. Consistently, specific knockdown of OSBPL6 in oligodendrocytes induced loss of myelin structure, while upregulating OSBPL6 or enhancing OSBPL6 transcription improved these impairments in depressive mice. Furthermore, restoring Cholesterol transport with β-cyclodextrin decreased Cholesterol accumulation, improved damaged myelin structure, and rescued depression-related behaviors in depressive mice.

Conclusions: These findings suggest that OSBPL6-mediated Cholesterol homeostasis in oligodendrocytes can promote myelin production against chronic stress-induced cerebral demyelination and depression with behavioral disorders.

Keywords

Cholesterol homeostasis; Demyelination; Depression; OSBPL6; Oligodendrocyte.

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