| Title | Aberrant oligodendroglial LDL receptor orchestrates demyelination in chronic cerebral ischemia |
| Authors | Xie, Yi Zhang, Xiaohao Xu, Pengfei Zhao, Nana Zhao, Ying Li, Yunzi Hong, Ye Peng, Mengna Yuan, Kang Wan, Ting Sun, Rui Chen, Deyan Xu, Lili Chen, Jingjing Guo, Hongquan Shan, Wanying Li, Juanji Li, Rongrong Xiong, Yunyun Liu, Dezhi Wang, Yuhui Liu, George Ye, Ruidong Liu, Xinfeng |
| Affiliation | Nanjing Univ, Affiliated Jinling Hosp, Dept Neurol, Sch Med, Nanjing, Jiangsu, Peoples R China Univ Sci & Technol China, Affiliated Hosp USTC, Div Life Sci & Med, Stroke Ctr, Hefei, Anhui, Peoples R China Univ Sci & Technol China, Affiliated Hosp USTC, Div Life Sci & Med, Dept Neurol, Hefei, Anhui, Peoples R China Nanjing Med Univ, Jinling Hosp, Dept Neurol, Nanjing, Jiangsu, Peoples R China Nanjing Univ, Ctr Publ Hlth Res, Sch Med, Nanjing, Jiangsu, Peoples R China Nanjing Med Univ, Dept Neurol, Nanjing Brain Hosp, Nanjing, Jiangsu, Peoples R China Southern Med Univ, Jinling Hosp, Dept Neurol, Nanjing, Jiangsu, Peoples R China China Natl Clin Res Ctr Neurol Dis, Beijing, Peoples R China Capital Med Univ, Beijing Tiantan Hosp, Dept Neurol, Vasc Neurol, Beijing, Peoples R China Shanghai Univ Tradit Chinese Med, Dept Neurol, Shuguang Hosp, Shanghai, Peoples R China Peking Univ, Sch Basic Med, Inst Cardiovasc Sci, Hlth Sci Ctr, Beijing, Peoples R China |
| Keywords | DENSITY-LIPOPROTEIN RECEPTOR CENTRAL-NERVOUS-SYSTEM WHITE-MATTER LESIONS CHOLESTEROL-METABOLISM CELL PROLIFERATION PROTEIN EXPRESSION SURVIVAL MAPK DIFFERENTIATION |
| Issue Date | 4-Jan-2021 |
| Publisher | JOURNAL OF CLINICAL INVESTIGATION |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/603306 |
| ISSN | 0021-9738 |
| DOI | 10.1172/JCI128114 |
| Indexed | SCI(E) |
| Appears in Collections: | 基础医学院 |
