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Neural Regeneration Research Feb 2024The myelin sheath is a lipoprotein-rich, multilayered structure capable of increasing conduction velocity in central and peripheral myelinated nerve fibers. Due to the... (Review)
Review
The myelin sheath is a lipoprotein-rich, multilayered structure capable of increasing conduction velocity in central and peripheral myelinated nerve fibers. Due to the complex structure and composition of myelin, various histological techniques have been developed over the centuries to evaluate myelin under normal, pathological or experimental conditions. Today, methods to assess myelin integrity or content are key tools in both clinical diagnosis and neuroscience research. In this review, we provide an updated summary of the composition and structure of the myelin sheath and discuss some histological procedures, from tissue fixation and processing techniques to the most used and practical myelin histological staining methods. Considering the lipoprotein nature of myelin, the main features and technical details of the different available methods that can be used to evaluate the lipid or protein components of myelin are described, as well as the precise ultrastructural techniques.
PubMed: 37488878
DOI: 10.4103/1673-5374.375318 -
European Journal of Medical Research Feb 2024Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the central nervous system (CNS). The underlying pathophysiology of MS is the... (Review)
Review
Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the central nervous system (CNS). The underlying pathophysiology of MS is the destruction of myelin sheath by immune cells. The formation of myelin plaques, inflammation, and injury of neuronal myelin sheath characterizes its neuropathology. MS plaques are multiple focal regions of demyelination disseminated in the brain's white matter, spinal cords, deep grey matter, and cerebral cortex. Fenofibrate is a peroxisome proliferative activated receptor alpha (PPAR-α) that attenuates the inflammatory reactions in MS. Fenofibrate inhibits differentiation of Th17 by inhibiting the expression of pro-inflammatory signaling. According to these findings, this review intended to illuminate the mechanistic immunoinflammatory role of fenofibrate in mitigating MS neuropathology. In conclusion, fenofibrate can attenuate MS neuropathology by modulating different pathways, including oxidative stress, autophagy, mitochondrial dysfunction, inflammatory-signaling pathways, and neuroinflammation.
Topics: Humans; Multiple Sclerosis; Fenofibrate; Central Nervous System; Neurons; Inflammation
PubMed: 38336772
DOI: 10.1186/s40001-024-01700-2 -
Nature Communications Dec 2023Oligodendrocyte precursor cells (OPCs) generate oligodendrocytes, contributing to myelination and myelin repair. OPCs contact axons and respond to neuronal activity, but...
Oligodendrocyte precursor cells (OPCs) generate oligodendrocytes, contributing to myelination and myelin repair. OPCs contact axons and respond to neuronal activity, but how the information relayed by the neuronal activity translates into OPC Ca signals, which in turn influence their fate, remains unknown. We generated transgenic mice for concomitant monitoring of OPCs Ca signals and cell fate using 2-photon microscopy in the somatosensory cortex of awake-behaving mice. Ca signals in OPCs mainly occur within processes and confine to Ca microdomains. A subpopulation of OPCs enhances Ca transients while mice engaged in exploratory locomotion. We found that OPCs responsive to locomotion preferentially differentiate into oligodendrocytes, and locomotion-non-responsive OPCs divide. Norepinephrine mediates locomotion-evoked Ca increases in OPCs by activating α1 adrenergic receptors, and chemogenetic activation of OPCs or noradrenergic neurons promotes OPC differentiation. Hence, we uncovered that for fate decisions OPCs integrate Ca signals, and norepinephrine is a potent regulator of OPC fate.
Topics: Mice; Animals; Calcium; Oligodendrocyte Precursor Cells; Norepinephrine; Mice, Transgenic; Myelin Sheath; Oligodendroglia; Cell Differentiation; Cerebral Cortex
PubMed: 38065932
DOI: 10.1038/s41467-023-43920-w -
International Journal of Molecular... Sep 2023(forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the gene that affect brain structure and function. Individuals affected by syndrome...
(forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the gene that affect brain structure and function. Individuals affected by syndrome frequently exhibit delayed myelination in neuroimaging studies, which may impair the rapid conduction of nerve impulses. To date, the specific effects of FOXG1 on oligodendrocyte lineage progression and myelination during early postnatal development remain unclear. Here, we investigated the effects of deficiency on myelin development in the mouse brain by conditional deletion of in neural progenitors using mice and tamoxifen induction at postnatal day 0 (P0). We found that deficiency resulted in a transient delay in myelination, evidenced by decreased myelin formation within the first two weeks after birth, but ultimately recovered to the control levels by P30. We also found that deletion prevented the timely attenuation of platelet-derived growth factor receptor alpha (PDGFRα) signaling and reduced the cell cycle exit of oligodendrocyte precursor cells (OPCs), leading to their excessive proliferation and delayed maturation. Additionally, deletion increased the expression of Hes5, a myelin formation inhibitor, as well as Olig2 and Sox10, two promoters of OPC differentiation. Our results reveal the important role of in myelin development and provide new clues for further exploring the pathological mechanisms of syndrome.
Topics: Animals; Mice; Brain; Rett Syndrome; Action Potentials; Cell Cycle; Cell Differentiation; Nerve Tissue Proteins; Forkhead Transcription Factors
PubMed: 37762220
DOI: 10.3390/ijms241813921 -
Aging and Disease May 2024In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of... (Review)
Review
In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases.
Topics: Humans; Microglia; Myelin Sheath; Animals; Demyelinating Diseases; Immunomodulation; Ion Channels; Remyelination; Reactive Oxygen Species
PubMed: 38029392
DOI: 10.14336/AD.2023.1107 -
Cellular and Molecular Life Sciences :... Apr 2024In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of... (Review)
Review
In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays a crucial role in the transmission of neuronal information by promoting the rapid saltatory conduction of action potentials and providing neurons with structural and metabolic support. Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally recognized as a universal evolutionary innovation to respond quickly to the environment: myelin helps us think and act fast. Nevertheless, the role of myelin in the central nervous system, especially in the brain, may not be primarily focused on accelerating conduction speed but rather on ensuring precision. Its principal function could be to coordinate various neuronal networks, promoting their synchronization through oscillations (or rhythms) relevant for specific information processing tasks. Interestingly, myelin has been directly involved in different types of cognitive processes relying on brain oscillations, and myelin plasticity is currently considered to be part of the fundamental mechanisms for memory formation and maintenance. However, despite ample evidence showing the involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully understood. In this review, we aim to highlight what is known and what remains to be explored to understand the role of myelin in high order brain processes.
Topics: Animals; Myelin Sheath; Cognition; Neurodevelopmental Disorders; Central Nervous System; Brain
PubMed: 38615095
DOI: 10.1007/s00018-024-05222-2 -
Neuroscience Feb 2024With the deepening of population aging, the treatment of cognitive impairment and dementia is facing increasing challenges. Vascular dementia (VaD) is a cognitive... (Review)
Review
With the deepening of population aging, the treatment of cognitive impairment and dementia is facing increasing challenges. Vascular dementia (VaD) is a cognitive dysfunction caused by brain blood flow damage and one of the most common causes of dementia after Alzheimer's disease. White matter damage in patients with chronic ischemic dementia often occurs before cognitive impairment, and its pathological changes include leukoaraiosis, myelin destruction and oligodendrocyte death. The pathophysiology of vascular dementia is complex, involving a variety of neuronal and vascular lesions. The current proposed mechanisms include calcium overload, oxidative stress, nitrative stress and inflammatory damage, which can lead to hypoxia-ischemia and demyelination. Oligodendrocytes are the only myelinating cells in the central nervous system and closely associated with VaD. In this review article, we intend to further discuss the role of oligodendrocytes in white matter and myelin injury in VaD and the development of anti-myelin injury target drugs.
Topics: Humans; Dementia, Vascular; White Matter; Oligodendroglia; Alzheimer Disease; Myelin Sheath
PubMed: 37913862
DOI: 10.1016/j.neuroscience.2023.10.018 -
Neurobiology of Disease Sep 2023The blood-nerve and myelin barrier shield peripheral neurons and their axons. These barriers are sealed by tight junction proteins, which control the passage of...
BACKGROUND
The blood-nerve and myelin barrier shield peripheral neurons and their axons. These barriers are sealed by tight junction proteins, which control the passage of potentially noxious molecules including proinflammatory cytokines via paracellular pathways. Peripheral nerve barrier breakdown occurs in various neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and traumatic neuropathy. Here, we studied the functional role of the tight junction protein claudin-12 in regulating peripheral nerve barrier integrity and CIDP pathogenesis.
METHODS
Sections from sural nerve biopsies from 23 patients with CIDP and non-inflammatory idiopathic polyneuropathy (PNP) were analyzed for claudin-12 and -19 immunoreactivity. Cldn12-KO mice were generated and subjected to the chronic constriction injury (CCI) model of neuropathy. These mice were then characterized using a battery of barrier and behavioral tests, histology, immunohistochemistry, and mRNA/protein expression. In phenotype rescue experiments, the proinflammatory cytokine TNFα was neutralized with the anti-TNFα antibody etanercept; the peripheral nerve barrier was stabilized with the sonic hedgehog agonist smoothened (SAG).
RESULTS
Compared to those without pain, patients with painful neuropathy exhibited reduced claudin-12 expression independently of fiber loss. Accordingly, global Cldn12-KO in male mice, but not fertile female mice, selectively caused mechanical allodynia associated with a leaky myelin barrier, increased TNFα, decreased sonic hedgehog (SHH), and loss of small axons accompanied by reduced peripheral myelin protein 22 (Pmp22). Other barriers and neurological functions remained intact. The Cldn12-KO phenotype could be rescued either by neutralizing TNFα with etanercept or stabilizing the barrier with SAG, which both also upregulated the Schwann cell barrier proteins Cldn19 and Pmp22.
CONCLUSION
These results point to a critical role for claudin-12 in maintaining the myelin barrier presumably via Pmp22 and highlight restoration of the hedgehog pathway as a potential treatment strategy for painful inflammatory neuropathy.
Topics: Animals; Female; Male; Mice; Claudins; Etanercept; Hedgehog Proteins; Myelin Sheath; Pain; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Tight Junction Proteins; Humans
PubMed: 37527762
DOI: 10.1016/j.nbd.2023.106246 -
Brain : a Journal of Neurology May 2024Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease,...
Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with ageing, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKγ from oligodendrocyte precursors. We found that p38γMAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38γMAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38γMAPK was enriched in multiple sclerosis lesions from patients. Oligodendrocyte progenitors expressed high levels of p38γMAPK in areas of failed remyelination but did not express detectable levels of p38γMAPK in areas where remyelination was apparent. Our data suggest that p38γ could be targeted to improve myelin repair in multiple sclerosis.
Topics: Animals; Remyelination; Multiple Sclerosis; Myelin Sheath; Mice; Oligodendroglia; Humans; Mitogen-Activated Protein Kinase 12; Cell Differentiation; Cuprizone; Mice, Inbred C57BL; Male; Female; Demyelinating Diseases; Oligodendrocyte Precursor Cells; Mice, Transgenic
PubMed: 38128553
DOI: 10.1093/brain/awad421 -
Proceedings of the National Academy of... Sep 2023The human endogenous retrovirus type W (HERV-W) has been identified and repeatedly confirmed as human-specific pathogenic entity affecting many cell types in multiple...
The human endogenous retrovirus type W (HERV-W) has been identified and repeatedly confirmed as human-specific pathogenic entity affecting many cell types in multiple sclerosis (MS). Our recent contributions revealed the encoded envelope (ENV) protein to disturb myelin repair by interfering with oligodendroglial precursor differentiation and by polarizing microglial cells toward an axon-damage phenotype. Indirect proof of ENV's antiregenerative and degenerative activities has been gathered recently in clinical trials using a neutralizing anti-ENV therapeutic antibody. Yet direct proof of its mode of action can only be presented here based on transgenic ENV expression in mice. Upon demyelination, we observed myelin repair deficits, neurotoxic microglia and astroglia, and increased axon degeneration. Experimental autoimmune encephalomyelitis activity progressed faster in mutant mice equally accompanied by activated glial cells. This study therefore provides direct evidence on HERV-W ENV's contribution to the overall negative impact of this activated viral entity in MS.
Topics: Humans; Animals; Mice; Endogenous Retroviruses; Neuroglia; Animals, Genetically Modified; Myelin Sheath; Multiple Sclerosis
PubMed: 37695891
DOI: 10.1073/pnas.2308187120