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 12

Reexpression of LDLR with NPVY motif rescues hypomyelination in Ldlr–/– mice.

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Reexpression of LDLR with NPVY motif rescues hypomyelination in Ldlr–/– ...
(A) Representative fluorescence images of the transfection of GFP (green) reporter lentiviruses into mature oligodendrocytes (GST-pi+, red) with re-expression of LDLR (dark blue, indicated by white arrows) in the CC of Ldlr–/– mice. (B) Images showing the proliferation of native OPCs (n = 4 in each group). (C) Quantification of the results in B. (D) Images showing the mature oligodendrocytes (CC1+ or GST-pi+ cells) in the CC (n = 4 in each group). (E) Quantification of the results in D. (F) Representative fiber tractographies of mice injected with 3 types of viruses. Eigenvector components were mapped to the following color schemes: red = left–right, blue = cranial–caudal, and green = dorsal–ventral directions (n = 3 in each group). (G and H) Quantification of the results in F. (I) MBP and MAG staining of the CC in Ldlr–/– mice receiving lentiviruses (n = 4 in each group). The CC boundary is indicated by the white dashed line. (J and K) Quantification of the results in I. Data presented as mean ± SD. *P < 0.05, **P < 0.01 vs. LV-control by 1-way ANOVA with Tukey’s post hoc test. Scale bars: 20 μm.