162 Chapter 7 inhibition of the oligodendrocyte cholesterol synthesis pathway in mice leads to a delay in myelination suggesting cholesterol production by oligodendrocytes and astrocytes is critical for early myelination69. This suggests that cholesterol availability is a rate-limiting factor in myelin production. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, the cholesterol synthesis pathway is downregulated in astrocytes of the cerebellum and spinal cord68. Determining whether this is a cause of limited remyelination requires more investigation. The metabolite exchange between oligodendrocytes and astrocytes may be key for astrocytic leukodystrophies, as disturbed astrocyte function in these disorders may limit lipid exchange from astrocytes to oligodendrocytes. Astrocytic communication with oligodendrocytes Blood-brain barrier interactions Astrocyte end-feet cover up to 90% of the brain vasculature and are exchange sites for nutrients, metabolites, and ions from the blood to the brain. BBB dysfunction is a key step in the pathogenesis of inflammatory and neurodegenerative CNS diseases70. Iron from the blood is provided by astrocytes to oligodendrocytes through endocytosis and transferred to the cells as protein-bound iron. Iron is essential for several enzymatic functions of oligodendrocytes, such as energy metabolism enzymes, including the mitochondrial respiratory chain protein complexes I-IV, which use it as a co-factor4,71. When oligodendrocytes are deprived of iron, proliferation and differentiation of OPCs is impaired as shown in vitro, leading to a delay in remyelination after injury in vivo71,72. The importance of iron in myelination is exemplified by prenatal iron deficiency in which abnormal oligodendrocyte distribution is observed72. Abnormalities in iron metabolism are also reported in MS71 and HD73 and restoration of normal metabolism is required for remyelination. Maintenance and development of theBBB is regulatedbyastrocytic Shh74. InMS, Shhacts as ananti-inflammatory molecule at the level of the neurovascular unit and is increased during neuroinflammation to promote BBB repair and integrity74. These examples underscore the critical role of astrocytes in BBB functioning in order to provide metabolic support to oligodendrocytes, essential in processes such as myelination. While astrocytes are considered to be key players in maintaining BBB integrity, OPCs have also been shown to play a role in BBB integrity through TGF-β signalling75. Additionally, BBB integrity is enhanced by OPCs through PDGF-BB/PDGFRα signalling while oligodendrocytes control BBB integrity independent of this pathway76. Conversely, a recent study combining pathology, in vivo and in vitro cultures indicates that clusters of OPCs contribute to altered vascular permeability by impacting the astrocyte foot processes in MS77. OPCs require a vascular scaffold for migration throughout the CNS to repopulate demyelinated areas in MS but detachment of the vasculature fails which results in a disruption of the BBB integrity77. Gap junctions connect astrocytes and oligodendrocytes Astrocytes are connected to other glial cells via gap junctions, allowing free flow of ions and small metabolites. Gap junctions between astrocytes are made up of connexin (Cx) 30 and/or 43 that forms either homotypic (Cx30:Cx30 or Cx43:Cx43) or heterotypic channels (Cx30:Cx43). Using these gap junctions, astrocytes form a syncytium with free flow of small molecules including gliotransmitters and lactate that aids buffering of K+23,78. Astrocytes express Cx30 and Cx43 that couples to adjacent oligodendrocytes expressing Cx32 and Cx47
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