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 decline of oligodendroglial LDLR with impaired oligodendroglial differentiation and survival. Oligodendroglial cholesterol levels, however, remained unchanged. Mice miR-344e-3p and human homolog miR-410-3p, two miRNAs directly targeting Ldlr, were identified in experimental and clinical leukoaraiosis, thus leading to LDLR reduction. Lentiviral delivery of LDLR ameliorated the demyelination following chronic cerebral ischemia. By contrast, Ldlr-/mice displayed inadequate myelination in the corpus callosum. Ldlr-/oligodendrocyte progenitor cells (OPCs) exhibited defective 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 phosphotyrosine binding domain of Shc, which subsequently activated 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.

Vascular endothelium deploys caveolin-1 to regulate oligodendrogenesis after chronic cerebral ischemia in mice

“…However, OPC maturation is often arrested in hypoxia/ischemia 6 . Our previous study, consistently, found robust OPC proliferation after chronic cerebral ischemia, but it was not durable and failed to restore myelination 7 . Thus, attempts to promote oligodendrogenesis may provide clues to ameliorate demyelination therapeutically.…”

“…However, along with the hypoperfusion, proliferated OPCs were increasingly gathered on the blood vessels, more like in a "traffic jam", with growing cluster frequency and size. The overwhelmed differentiation of endogenous OPCs may act in concert with increased oligodendrocyte death 7 , leading to a significant decline in premyelinating and mature oligodendrocytes at 4 weeks after BCAS. The OPC clustering not only suggested a substantial defect in singlecell perivascular interaction but also indicated vascular detachment failure, which may disturb OPC dispersal in the area of demyelination.…”

“…White matter LFB staining was carried out with the degree of white matter damage scored 7,51 and Black-gold II staining (Sigma-Aldrich, USA) was performed with the calculation of myelinated area 64 .…”

BK Channel-Mediated Microglial Phagocytosis Alleviates Neurological Deficit After Ischemic Stroke

“…Inhibition of ERK promoted HMGB1-mediated neuronal death in vitro ( Kim et al, 2011 ). ERK1/2 was involved in promoting neuronal survival and differentiation ( Tejeda and Diaz-Guerra, 2017 ; Xie et al, 2020 ). After ischemic stroke, cell debris of injury induce microglial phagocytosis via the TREM-2/DAP12/ERK/PKC pathway ( Fu et al, 2014 ).…”

6-Thioguanine Inhibits Herpes Simplex Virus 1 Infection of Eyes

“…Formalin-fixed, paraffin-embedded tissue sections (5 mm in thickness) mounted on glass slides were used for various staining. The H&E staining was performed as previously described ( 48 ). For immunofluorescence, the mouse corneal tissue sections were cryosectioned, blocked, and then stained with goat anti-rabbit Rac1 antibody (lot number 24072-1; ProteinTech), and HSK patient corneal tissue sections were stained with goat anti-rabbit Rac1 antibody (lot number 24072-1; ProteinTech).…”