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Physiological Reviews Jul 2019Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently,... (Review)
Review
Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently, saltatory nerve conduction was considered the only purpose of myelin, but it is now clear that myelin has more functions. In fact, myelinating oligodendrocytes are embedded in a vast network of interconnected glial and neuronal cells, and increasing evidence supports an active role of oligodendrocytes within this assembly, for example, by providing metabolic support to neurons, by regulating ion and water homeostasis, and by adapting to activity-dependent neuronal signals. The molecular complexity governing these interactions requires an in-depth molecular understanding of how oligodendrocytes and axons interact and how they generate, maintain, and remodel their myelin sheaths. This review deals with the biology of myelin, the expanded relationship of myelin with its underlying axons and the neighboring cells, and its disturbances in various diseases such as multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. Furthermore, we will highlight how specific interactions between astrocytes, oligodendrocytes, and microglia contribute to demyelination in hereditary white matter pathologies.
Topics: Aging; Animals; Central Nervous System; Demyelinating Diseases; Humans; Myelin Sheath
PubMed: 31066630
DOI: 10.1152/physrev.00031.2018 -
Cold Spring Harbor Perspectives in... Jun 2015Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin... (Review)
Review
Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons.
Topics: Axons; Glycolysis; Models, Biological; Myelin Sheath; Oligodendroglia; Synaptic Transmission
PubMed: 26101081
DOI: 10.1101/cshperspect.a020479 -
Cold Spring Harbor Perspectives in... Aug 2015Oligodendrocyte precursor cells (OPCs) originate in the ventricular zones (VZs) of the brain and spinal cord and migrate throughout the developing central nervous system... (Review)
Review
Oligodendrocyte precursor cells (OPCs) originate in the ventricular zones (VZs) of the brain and spinal cord and migrate throughout the developing central nervous system (CNS) before differentiating into myelinating oligodendrocytes (OLs). It is not known whether OPCs or OLs from different parts of the VZ are functionally distinct. OPCs persist in the postnatal CNS, where they continue to divide and generate myelinating OLs at a decreasing rate throughout adult life in rodents. Adult OPCs respond to injury or disease by accelerating their cell cycle and increasing production of OLs to replace lost myelin. They also form synapses with unmyelinated axons and respond to electrical activity in those axons by generating more OLs and myelin locally. This experience-dependent "adaptive" myelination is important in some forms of plasticity and learning, for example, motor learning. We review the control of OL lineage development, including OL population dynamics and adaptive myelination in the adult CNS.
Topics: Animals; Brain; Homeostasis; Intercellular Signaling Peptides and Proteins; Mammals; Myelin Sheath; Oligodendroglia; Spinal Cord; Synaptic Transmission
PubMed: 26492571
DOI: 10.1101/cshperspect.a020453 -
Cells Mar 2020Myelin is critical for the proper function of the nervous system and one of the most complex cell-cell interactions of the body. Myelination allows for the rapid... (Review)
Review
Myelin is critical for the proper function of the nervous system and one of the most complex cell-cell interactions of the body. Myelination allows for the rapid conduction of action potentials along axonal fibers and provides physical and trophic support to neurons. Myelin contains a high content of lipids, and the formation of the myelin sheath requires high levels of fatty acid and lipid synthesis, together with uptake of extracellular fatty acids. Recent studies have further advanced our understanding of the metabolism and functions of myelin fatty acids and lipids. In this review, we present an overview of the basic biology of myelin lipids and recent insights on the regulation of fatty acid metabolism and functions in myelinating cells. In addition, this review may serve to provide a foundation for future research characterizing the role of fatty acids and lipids in myelin biology and metabolic disorders affecting the central and peripheral nervous system.
Topics: Animals; Fatty Acids; Humans; Lipid Metabolism; Models, Biological; Myelin Sheath; Oxidation-Reduction
PubMed: 32230947
DOI: 10.3390/cells9040812 -
Cold Spring Harbor Perspectives in... Jun 2015Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between... (Review)
Review
Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between axons and Schwann cells. Extrinsic signals from the axon, and the extracellular matrix, drive Schwann cells to adopt a myelinating fate, whereas myelination reorganizes the axon for its role in conduction and is essential for its integrity. Here, we review our current understanding of the development, molecular organization, and function of myelinating Schwann cells. Recent findings into the extrinsic signals that drive Schwann cell myelination, their cognate receptors, and the downstream intracellular signaling pathways they activate will be described. Together, these studies provide important new insights into how these pathways converge to activate the transcriptional cascade of myelination and remodel the actin cytoskeleton that is critical for morphogenesis of the myelin sheath.
Topics: Action Potentials; Epigenesis, Genetic; Humans; Myelin Sheath; Nerve Fibers, Myelinated; Schwann Cells; Signal Transduction; Transcription, Genetic
PubMed: 26054742
DOI: 10.1101/cshperspect.a020529 -
Neuron Jul 2021Severe cognitive decline is a hallmark of Alzheimer's disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD...
Severe cognitive decline is a hallmark of Alzheimer's disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD patients. Here, we characterized the dynamics of myelin generation and loss in the APP/PS1 mouse model of AD. Unexpectedly, we observed a dramatic increase in the rate of new myelin formation in APP/PS1 mice, reminiscent of the robust oligodendroglial response to demyelination. Despite this increase, overall levels of myelination are decreased in the cortex and hippocampus of APP/PS1 mice and postmortem AD tissue. Genetically or pharmacologically enhancing myelin renewal, by oligodendroglial deletion of the muscarinic M1 receptor or systemic administration of the pro-myelinating drug clemastine, improved the performance of APP/PS1 mice in memory-related tasks and increased hippocampal sharp wave ripples. Taken together, these results demonstrate the potential of enhancing myelination as a therapeutic strategy to alleviate AD-related cognitive impairment.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Cognitive Dysfunction; Disease Models, Animal; Maze Learning; Mice; Mice, Transgenic; Myelin Sheath; Presenilin-1
PubMed: 34102111
DOI: 10.1016/j.neuron.2021.05.012 -
Acta Neuropathologica Communications Mar 2018Alzheimer's disease (AD) is conceptualized as a progressive consequence of two hallmark pathological changes in grey matter: extracellular amyloid plaques and... (Review)
Review
Alzheimer's disease (AD) is conceptualized as a progressive consequence of two hallmark pathological changes in grey matter: extracellular amyloid plaques and neurofibrillary tangles. However, over the past several years, neuroimaging studies have implicated micro- and macrostructural abnormalities in white matter in the risk and progression of AD, suggesting that in addition to the neuronal pathology characteristic of the disease, white matter degeneration and demyelination may be also important pathophysiological features. Here we review the evidence for white matter abnormalities in AD with a focus on myelin and oligodendrocytes, the only source of myelination in the central nervous system, and discuss the relationship between white matter changes and the hallmarks of Alzheimer's disease. We review several mechanisms such as ischemia, oxidative stress, excitotoxicity, iron overload, Aβ toxicity and tauopathy, which could affect oligodendrocytes. We conclude that white matter abnormalities, and in particular myelin and oligodendrocytes, could be mechanistically important in AD pathology and could be potential treatment targets.
Topics: Alzheimer Disease; Animals; Humans; Myelin Sheath; White Matter
PubMed: 29499767
DOI: 10.1186/s40478-018-0515-3 -
Neurotherapeutics : the Journal of the... Oct 2021Myelin is a key evolutionary specialization and adaptation of vertebrates formed by the plasma membrane of glial cells, which insulate axons in the nervous system.... (Review)
Review
Myelin is a key evolutionary specialization and adaptation of vertebrates formed by the plasma membrane of glial cells, which insulate axons in the nervous system. Myelination not only allows rapid and efficient transmission of electric impulses in the axon by decreasing capacitance and increasing resistance but also influences axonal metabolism and the plasticity of neural circuits. In this review, we will focus on Schwann cells, the glial cells which form myelin in the peripheral nervous system. Here, we will describe the main extrinsic and intrinsic signals inducing Schwann cell differentiation and myelination and how myelin biogenesis is achieved. Finally, we will also discuss how the study of human disorders in which molecules and pathways relevant for myelination are altered has enormously contributed to the current knowledge on myelin biology.
Topics: Animals; Axons; Biology; Humans; Myelin Sheath; Neuroglia; Schwann Cells
PubMed: 34244924
DOI: 10.1007/s13311-021-01083-w -
Current Biology : CB Oct 2016Myelin is a key evolutionary acquisition that underlay the development of the large, complex nervous systems of all hinged-jaw vertebrates. By promoting rapid, efficient...
Myelin is a key evolutionary acquisition that underlay the development of the large, complex nervous systems of all hinged-jaw vertebrates. By promoting rapid, efficient nerve conduction, myelination also made possible the development of the large body size of these vertebrates. In addition to increasing the speed of nerve conduction, myelination has emerged as a source of plasticity in neural circuits that is crucial for proper timing and function. Here, we briefly describe the organization of myelin and of myelinated axons, as well as the functions of myelin in nerve conduction and neural circuits, and consider its potential evolutionary origins.
Topics: Animals; Axons; Biological Evolution; Myelin Sheath; Nerve Fibers, Myelinated; Neural Conduction; Vertebrates
PubMed: 27780071
DOI: 10.1016/j.cub.2016.07.074 -
Nature Feb 2019Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths. Myelin is destroyed by the immune...
Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process. Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans, it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of C derived from nuclear testing in genomic DNA, we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques-thinly myelinated lesions that are thought to represent remyelinated areas-were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies.
Topics: Adult; Age of Onset; Aging; Case-Control Studies; Cell Differentiation; Cell Proliferation; Cell Separation; Female; Humans; Male; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Remyelination; White Matter
PubMed: 30675058
DOI: 10.1038/s41586-018-0842-3