-
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 -
Cells Nov 2019Oligodendrocytes are the myelinating cells of the central nervous system (CNS) that are generated from oligodendrocyte progenitor cells (OPC). OPC are distributed... (Review)
Review
Oligodendrocytes are the myelinating cells of the central nervous system (CNS) that are generated from oligodendrocyte progenitor cells (OPC). OPC are distributed throughout the CNS and represent a pool of migratory and proliferative adult progenitor cells that can differentiate into oligodendrocytes. The central function of oligodendrocytes is to generate myelin, which is an extended membrane from the cell that wraps tightly around axons. Due to this energy consuming process and the associated high metabolic turnover oligodendrocytes are vulnerable to cytotoxic and excitotoxic factors. Oligodendrocyte pathology is therefore evident in a range of disorders including multiple sclerosis, schizophrenia and Alzheimer's disease. Deceased oligodendrocytes can be replenished from the adult OPC pool and lost myelin can be regenerated during remyelination, which can prevent axonal degeneration and can restore function. Cell population studies have recently identified novel immunomodulatory functions of oligodendrocytes, the implications of which, e.g., for diseases with primary oligodendrocyte pathology, are not yet clear. Here, we review the journey of oligodendrocytes from the embryonic stage to their role in homeostasis and their fate in disease. We will also discuss the most common models used to study oligodendrocytes and describe newly discovered functions of oligodendrocytes.
Topics: Alzheimer Disease; Animals; Humans; Multiple Sclerosis; Myelin Sheath; Oligodendrocyte Precursor Cells; Oligodendroglia; Remyelination; Schizophrenia
PubMed: 31726662
DOI: 10.3390/cells8111424 -
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 -
Nature Nov 2022APOE4 is the strongest genetic risk factor for Alzheimer's disease. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to...
APOE4 is the strongest genetic risk factor for Alzheimer's disease. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.
Topics: Animals; Humans; Mice; Alzheimer Disease; Apolipoprotein E4; Brain; Cholesterol; Oligodendroglia; Nerve Fibers, Myelinated; Autopsy; Induced Pluripotent Stem Cells; Neurons; Heterozygote; Biological Transport; Homeostasis; Single-Cell Analysis; Memory; Aging; Gene Expression Profiling; Myelin Sheath
PubMed: 36385529
DOI: 10.1038/s41586-022-05439-w -
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... 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 -
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 -
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 -
Cellular and Molecular Life Sciences :... Oct 2020The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve... (Review)
Review
The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve regeneration following traumatic injuries and peripheral neuropathies. After a nerve damage, SCs are rapidly activated by injury-induced signals and respond by entering the repair program. During the repair program, SCs undergo dynamic cell reprogramming and morphogenic changes aimed at promoting nerve regeneration and functional recovery. SCs convert into a repair phenotype, activate negative regulators of myelination and demyelinate the damaged nerve. Moreover, they express many genes typical of their immature state as well as numerous de-novo genes. These genes modulate and drive the regeneration process by promoting neuronal survival, damaged axon disintegration, myelin clearance, axonal regrowth and guidance to their former target, and by finally remyelinating the regenerated axon. Many signaling pathways, transcriptional regulators and epigenetic mechanisms regulate these events. In this review, we discuss the main steps of the repair program with a particular focus on the molecular mechanisms that regulate SC plasticity following peripheral nerve injury.
Topics: Animals; Axons; Cell Plasticity; Humans; Myelin Sheath; Nerve Regeneration; Peripheral Nerve Injuries; Schwann Cells; Sciatic Nerve; Signal Transduction
PubMed: 32277262
DOI: 10.1007/s00018-020-03516-9 -
Nature Feb 2019Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple...
Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination, which suggests that other factors contribute to this variability. One such factor may be oligodendrocyte heterogeneity. Not all oligodendrocytes are the same-those from the mouse spinal cord inherently produce longer myelin sheaths than those from the cortex, and single-cell analysis of the mouse central nervous system identified further differences. However, the extent of human oligodendrocyte heterogeneity and its possible contribution to MS pathology remain unknown. Here we performed single-nucleus RNA sequencing from white matter areas of post-mortem human brain from patients with MS and from unaffected controls. We identified subclusters of oligodendroglia in control human white matter, some with similarities to mouse, and defined new markers for these cell states. Notably, some subclusters were underrepresented in MS tissue, whereas others were more prevalent. These differences in mature oligodendrocyte subclusters may indicate different functional states of oligodendrocytes in MS lesions. We found similar changes in normal-appearing white matter, showing that MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important for understanding disease progression and developing therapeutic approaches.
Topics: Adult; Aged; Aged, 80 and over; Animals; Autopsy; Biomarkers; Brain; Case-Control Studies; Disease Progression; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Male; Mice; Middle Aged; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Remyelination; Sequence Analysis, RNA; Transcription, Genetic; White Matter
PubMed: 30747918
DOI: 10.1038/s41586-019-0903-2