Aberrant oligodendroglial LDL receptor orchestrates demyelination in chronic cerebral ischemia
Yi Xie, … , Ruidong Ye, Xinfeng Liu
Yi Xie, … , Ruidong Ye, Xinfeng Liu
Published November 3, 2020
Citation Information: J Clin Invest. 2021;131(1):e128114. https://doi.org/10.1172/JCI128114.
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Research Article Cell biology Neuroscience

Aberrant oligodendroglial LDL receptor orchestrates demyelination in chronic cerebral ischemia

Abstract

Oligodendrocytes express low-density lipoprotein receptor (LDLR) to endocytose cholesterol for the maintenance of adulthood myelination. However, the potential role of LDLR in chronic cerebral ischemia–related demyelination remains unclear. We used bilateral carotid artery stenosis (BCAS) to induce sustained cerebral ischemia in mice. This hypoxic-ischemic injury caused a remarkable decrease in oligodendroglial LDLR, with impaired oligodendroglial differentiation and survival. Oligodendroglial cholesterol levels, however, remained unchanged. Mouse miR-344e-3p and the human homolog miR-410-3p, 2 miRNAs directly targeting Ldlr, were identified in experimental and clinical leukoaraiosis and were thus implicated in the LDLR reduction. Lentiviral delivery of LDLR ameliorated demyelination following chronic cerebral ischemia. By contrast, Ldlr–/– mice displayed inadequate myelination in the corpus callosum. Ldlr–/– oligodendrocyte progenitor cells (OPCs) exhibited reduced ability to differentiate and myelinate axons in vitro. Transplantation with Ldlr–/– OPCs could not rescue the BCAS-induced demyelination. Such LDLR-dependent myelin restoration might involve a physical interaction of the Asn-Pro-Val-Tyr (NPVY) motif with the phosphotyrosine binding domain of Shc, which subsequently activated the MEK/ERK pathway. Together, our findings demonstrate that the aberrant oligodendroglial LDLR in chronic cerebral ischemia impairs myelination through intracellular signal transduction. Preservation of oligodendroglial LDLR may provide a promising approach to treat ischemic demyelination.

Authors

Yi Xie, Xiaohao Zhang, Pengfei Xu, Nana Zhao, Ying Zhao, Yunzi Li, Ye Hong, Mengna Peng, Kang Yuan, Ting Wan, Rui Sun, Deyan Chen, Lili Xu, Jingjing Chen, Hongquan Guo, Wanying Shan, Juanji Li, Rongrong Li, Yunyun Xiong, Dezhi Liu, Yuhui Wang, George Liu, Ruidong Ye, Xinfeng Liu

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Figure 5

miR-344e/410-3p regulates Ldlr expression and cell differentiation in OPCs.

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miR-344e/410-3p regulates Ldlr expression and cell differentiation in OP...
(A and B) Dual-luciferase reporter assay of the relationship between miR-344e/410-3p mimic and WT 3′ UTR of mouse/human Ldlr (n = 8 experiments). N.C., negative control. (C) Uptake of miR-410-3p agomir or antagomir in cultured OPCs. NG2, neuron-glial antigen 2. (D–F) The endogenous expression of LDLR mRNA and protein after treatment with miR-410-3p agomir and antagomir (n ≥ 3 experiments). (G and H) Representative immunofluorescence images and quantification showing the mature MBP+ oligodendrocytes differentiated from OPCs after treatment with miR-410-3p agomir or antagomir (n = 4 experiments). (I) Western blotting showing the expression of myelin proteins MBP and CNPase (n = 3 experiments). (J and K) Quantification of the results in I. Data presented as mean ± SD. *P < 0.05, **P < 0.01 vs. controls by paired t test (B) or 1-way ANOVA with Tukey’s post hoc test (D, F, H, I, and K). Scale bars: 20 μm.