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Nature Jan 2023Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in...
Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1-TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease.
Topics: Adult; Animals; Humans; Mice; Axons; Central Nervous System; Microglia; Myelin Sheath; Neurodegenerative Diseases; Oligodendroglia; Cognition; Transforming Growth Factor beta1; Receptor, Transforming Growth Factor-beta Type I; Lipid Metabolism; Aging
PubMed: 36517604
DOI: 10.1038/s41586-022-05534-y -
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 -
Nature Jun 2023The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly...
The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter of which is associated with secondary neuroinflammation. As oligodendrocytes support axonal energy metabolism and neuronal health, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.
Topics: Animals; Mice; Alzheimer Disease; Amyloid beta-Peptides; Disease Models, Animal; Myelin Sheath; Plaque, Amyloid; Axons; Microglia; Single-Cell Gene Expression Analysis; Risk Factors; Disease Progression
PubMed: 37258678
DOI: 10.1038/s41586-023-06120-6 -
Journal of Neuroscience Research May 2020Traumatic peripheral nerve injury represents a major clinical and public health problem that often leads to significant functional impairment and permanent disability.... (Review)
Review
Traumatic peripheral nerve injury represents a major clinical and public health problem that often leads to significant functional impairment and permanent disability. Despite modern diagnostic procedures and advanced microsurgical techniques, functional recovery after peripheral nerve repair is often unsatisfactory. Therefore, there is an unmet need for new therapeutic or adjunctive strategies to promote the functional recovery in nerve injury patients. In contrast to the central nervous system, Schwann cells in the peripheral nervous system play a pivotal role in several aspects of nerve repair such as degeneration, remyelination, and axonal growth. Several non-surgical approaches, including pharmacological, electrical, cell-based, and laser therapies, have been employed to promote myelination and enhance functional recovery after peripheral nerve injury. This review will succinctly discuss the potential therapeutic strategies in the context of myelination following peripheral neurotrauma.
Topics: Animals; Humans; Myelin Sheath; Nerve Regeneration; Peripheral Nerve Injuries; Recovery of Function
PubMed: 31608497
DOI: 10.1002/jnr.24538 -
Nature Reviews. Neuroscience Dec 2020Throughout our lifespan, new sensory experiences and learning continually shape our neuronal circuits to form new memories. Plasticity at the level of synapses has been... (Review)
Review
Throughout our lifespan, new sensory experiences and learning continually shape our neuronal circuits to form new memories. Plasticity at the level of synapses has been recognized and studied for decades, but recent work has revealed an additional form of plasticity - affecting oligodendrocytes and the myelin sheaths they produce - that plays a crucial role in learning and memory. In this Review, we summarize recent work characterizing plasticity in the oligodendrocyte lineage following sensory experience and learning, the physiological and behavioural consequences of manipulating that plasticity, and the evidence for oligodendrocyte and myelin dysfunction in neurodevelopmental disorders with cognitive symptoms. We also discuss the limitations of existing approaches and the conceptual and technical advances that are needed to move forward this rapidly developing field.
Topics: Animals; Demyelinating Diseases; Humans; Learning; Memory; Myelin Sheath; Neuronal Plasticity; Oligodendroglia; Synapses
PubMed: 33046886
DOI: 10.1038/s41583-020-00379-8 -
Cell Metabolism Dec 2023The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on...
The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.
Topics: Peripheral Nerves; Myelin Sheath; Neuroglia; Schwann Cells; Nerve Regeneration
PubMed: 37989315
DOI: 10.1016/j.cmet.2023.10.017 -
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 -
Proceedings of the National Academy of... Oct 2019Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and...
Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.
Topics: Animals; Axons; Myelin Sheath; Nerve Regeneration; Peripheral Nerve Injuries; Rats
PubMed: 31611410
DOI: 10.1073/pnas.1910292116 -
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