Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation, phagolysosomal membrane rupture, and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters including apolipoprotein E. Remarkably, stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals thereby inducing a maladaptive immune response that impedes tissue regeneration.
Showing posts with label myelin. Show all posts
Showing posts with label myelin. Show all posts
Signalling through AMPA receptors on oligodendrocyte precursors promotes myelination by enhancing oligodendrocyte survival | eLife
Myelin, made by oligodendrocytes, is essential for rapid information transfer in the central nervous system. Oligodendrocyte precursors (OPs) receive glutamatergic synaptic input from axons but how this affects their development is unclear. Murine OPs in white matter express AMPA receptor (AMPAR) subunits GluA2, GluA3 and GluA4. We generated mice in which OPs lack both GluA2 and GluA3, or all three subunits GluA2/3/4, which respectively reduced or abolished AMPAR-mediated input to OPs. In both double- and triple-knockouts OP proliferation and number were unchanged but ~25% fewer oligodendrocytes survived in the subcortical white matter during development. In triple knockouts, this shortfall persisted into adulthood. The oligodendrocyte deficit resulted in ~20% fewer myelin sheaths but the average length, number and thickness of myelin internodes made by individual oligodendrocytes appeared normal. Thus, AMPAR-mediated signalling from active axons stimulates myelin production in developing white matter by enhancing oligodendrocyte survival, without influencing myelin synthesis per se.
Fetal Exposure to Antidepressants May Alter Corpus Callosum Microstructure
Selective serotonin reuptake inhibitors (SSRIs) may affecting white-matter brain development and alter the development of the fetal corpus callosum, according to results of a prospective study presented at the 2017 Annual Meeting of the Pediatric Academic Societies/American Society of Pediatric Nephrology (PAS/ASPN).
Translational Psychiatry - Regulation of prefrontal cortex myelination by the microbiota
"The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC."
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Do Gut Bugs Put the Brakes on Myelination? | The Translational Microbiome Research Forum
"Gut bacteria may play a role in regulating myelination in the prefrontal cortex (PFC), researchers reported here.
Microbe-free mice had greater expression of myelin-related genes and hypermyelination in the PFC compared with control animals, Alan Hoban, PhD, of University College Cork in Ireland, and colleagues presented at a poster session at the Society for Neuroscience meeting ."
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Microbe-free mice had greater expression of myelin-related genes and hypermyelination in the PFC compared with control animals, Alan Hoban, PhD, of University College Cork in Ireland, and colleagues presented at a poster session at the Society for Neuroscience meeting ."
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Mutation of 3-Hydroxy-3-Methylglutaryl CoA Synthase I Reveals Requirements for Isoprenoid and Cholesterol Synthesis in Oligodendrocyte Migration Arrest, Axon Wrapping, and Myelin Gene Expression
Myelin membrane, which ensheaths axons, has an unusually high amount of cholesterol. Cholesterol influences membrane fluidity and assembles lipid-rich microdomains within membranes, and some studies have shown that cholesterol is important for myelination. How cholesterol influences the development and differentiation of oligodendrocytes, glial cells that make myelin, is
not known nor is clear whether isoprenoids, which also are products of the cholesterol biosynthetic pathway, contribute to myelination. Through a forward genetic screen in zebrafish we
discovered that mutation of hmgcs1, which encodes an enzyme necessary for isoprenoid and cholesterol synthesis, causes oligodendrocyte progenitor cells (OPCs) to migrate past their target axons and to fail to express myelin genes. Drawing on a combination of pharmacological inhibitor and rescue experiments, we provide evidence that isoprenoids and protein prenylation, but not cholesterol, are required in OPCs to halt their migration at target axons. On the other hand, cholesterol, but not isoprenoids, is necessary both for axon ensheathment and myelin gene expression. Our data reveal that different products of the cholesterol biosynthetic pathway have distinct roles in oligodendrocyte development and that they together help to coordinate directed migration, axon wrapping, and gene expression.
not known nor is clear whether isoprenoids, which also are products of the cholesterol biosynthetic pathway, contribute to myelination. Through a forward genetic screen in zebrafish we
discovered that mutation of hmgcs1, which encodes an enzyme necessary for isoprenoid and cholesterol synthesis, causes oligodendrocyte progenitor cells (OPCs) to migrate past their target axons and to fail to express myelin genes. Drawing on a combination of pharmacological inhibitor and rescue experiments, we provide evidence that isoprenoids and protein prenylation, but not cholesterol, are required in OPCs to halt their migration at target axons. On the other hand, cholesterol, but not isoprenoids, is necessary both for axon ensheathment and myelin gene expression. Our data reveal that different products of the cholesterol biosynthetic pathway have distinct roles in oligodendrocyte development and that they together help to coordinate directed migration, axon wrapping, and gene expression.
Differences in the right inferior longitudinal fasciculus but no general disruption of white matter tracts in children with autism spectrum disorder
One of the most widely cited features of the neural phenotype of autism is reduced “integrity” of long-range white matter tracts, a claim based primarily on diffusion imaging studies. However, many prior studies have small sample sizes and/or fail to address differences in data quality between those with autism spectrum disorder (ASD) and typical participants, and there is little consensus on which tracts are affected. To overcome these problems, we scanned a large sample of children with autism
(n = 52) and typically developing children (n = 73). Data quality was variable, and worse in the ASD group, with some scans unusable because of head motion artifacts.
When we follow standard data analysis practices (i.e., without matching head motion between groups), we replicate the finding of lower fractional anisotropy (FA) in multiple white matter tracts. However, when we carefully match data quality between groups, all these effects disappear except in one tract, the right inferior longitudinal fasciculus (ILF).
Additional analyses showed the expected developmental increases in the FA of fiber tracts within ASD and typical groups individually, demonstrating that we had sufficient statistical power
to detect known group differences. Our data challenge the widely claimed general
disruption of white matter tracts in autism, instead implicating only one tract, the right ILF, in the ASD phenotype.
(n = 52) and typically developing children (n = 73). Data quality was variable, and worse in the ASD group, with some scans unusable because of head motion artifacts.
When we follow standard data analysis practices (i.e., without matching head motion between groups), we replicate the finding of lower fractional anisotropy (FA) in multiple white matter tracts. However, when we carefully match data quality between groups, all these effects disappear except in one tract, the right inferior longitudinal fasciculus (ILF).
Additional analyses showed the expected developmental increases in the FA of fiber tracts within ASD and typical groups individually, demonstrating that we had sufficient statistical power
to detect known group differences. Our data challenge the widely claimed general
disruption of white matter tracts in autism, instead implicating only one tract, the right ILF, in the ASD phenotype.
How the brain makes myelination activity-dependent
(Medical Xpress)—A major question regarding how axons acquire a coat of myelin, is the role of spiking activity. It is known that in culture systems oligodendroctyes will at least try to wrap anything that feels like an axon—even dead axons and artificial tubes. As axons acquire additional layers of myelin they conduct signals faster, and presumably become more efficient. It would therefore seem logical that the nervous system should apportion the most myelin to those neurons that are seeing the greatest activity. In that way the brain gets the most bang for its buck, energetically speaking. A new study in PLOS Biology suggests that while myelination is in many cases activity-independent at first, neurons can significantly ramp things up by flipping various molecular switches, one which appears to be Neuregulin (NRG1).
PLOS Biology: Neuregulin and BDNF Induce a Switch to NMDA Receptor-Dependent Myelination by Oligodendrocytes
Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.
Down-regulation of Myelin Gene Expression in Human Oligodendrocytes by Nitric Oxide: Implications for Demyelination in Multiple Sclerosis.
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS) with unknown etiology. Several studies have shown that demyelination in MS is caused by proinflammatory mediators and nitric oxide (NO), which is released by perivascular infiltrates and/or activated glial cells. Both endogenous NO released by microglia and astrocytes; and NO generated from exogenous NO donors are known to induce oligodendrocytes death. However, the molecular mechanism of oligodendroglial death is poorly understood. Here we explore the role of NO in modulating the expression of myelin-specific genes that leads to oligodendroglial death. We investigated the effect of NO on the expression of myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) in human primary oligodendrocytes. Combination of IFN-γ and bacterial lipopolysaccharide (LPS) or double stranded RNA in the form of polyIC induced the production of NO and decreased the expression of myelin gene in human fetal mixed glial cultures. Either a scavenger of NO (PTIO) or an inhibitor of inducible nitric oxide synthase (L-NIL) abrogated (LPS+IFN-γ)- and polyIC-mediated suppression of myelin genes in human mixed glial cells. The role of NO was further corroborated by the inhibition of myelin gene expression in purified human oligodendroglia by several NO donors including SNP, NOC-7, SIN-1, and SNAP. This study illustrates a novel biological role of NO in down-regulating the expression of myelin genes preceding the death of oligodendrocytes.
MicroRNA-23a promotes myelination in the central nervous system
Demyelinating disorders including leukodystrophies are devastating conditions that are still in need of better understanding, and both oligodendrocyte differentiation and myelin synthesis pathways are potential avenues for developing treatment. Overexpression of lamin B1 leads to leukodystrophy characterized by demyelination of the central nervous system, and microRNA-23 (miR-23) was found to suppress lamin B1 and enhance oligodendrocyte differentiation in vitro. Here, we demonstrated that miR-23a–overexpressing mice have increased myelin thickness, providing in vivo evidence that miR-23a enhances both oligodendrocyte differentiation and myelin synthesis. Using this mouse model, we explored possible miR-23atargets and revealed that the phosphatase and tensin homologue/phosphatidylinositol trisphosphate kinase/Akt/mammalian target of rapamycin pathway is modulated by miR-23a. Additionally, a long noncoding RNA, 2700046G09Rik, was identified as a miR-23a target and modulates phosphatase and tensin homologue itself in a miR-23a–dependent manner. The data presented here imply a unique role for miR-23ain the coordination of proteins and noncoding RNAs in generating and maintaining healthy myelin.
Infections in newborns linked to later behavior problems
"Researchers exploring the link between newborn infections and later behavior and movement problems have found that inflammation in the brain keeps cells from accessing iron at a critical time in brain development."Specific cells in the brain need iron to produce the white matter that ensures efficient communication among cells in the central nervous system. White matter refers to white-colored bundles of myelin, a protective coating on the axons that project from the main body of a brain cell.
Lithium in brain white matter
Lichtinger's results are surprising: Only in the samples of a depressive patient treated with lithium did he observe a higher accumulation of lithium in the so-called white matter. This is the area in the brain where nerve tracts run. The lithium content in the neighboring grey matter was 3 to 4 times lower. Lithium accumulation in white matter was not observed in a number of untreated depressive patients. This points to the fact that lithium does not work in the space between nerve cells, like other psychotropic drugs, but within the nerve tracts themselves.
Upregulation of ciliary neurotrophic factor in astrocytes by aspirin: Implications for remyelination in multiple sclerosis
Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor and mechanisms by which CNTF expression could be increased in the brain are poorly understood. Aspirin, acetylsalicylic acid, is one of the most widely-used analgesics. Interestingly, aspirin increased mRNA and protein expression of CNTF in primary mouse and human astrocytes in a dose- and time-dependent manner. Aspirin induced the activation of protein kinase A (PKA), but not protein kinase C (PKC). H-89, an inhibitor of PKA, abrogated aspirin-induced expression of CNTF. The activation of cAMP response element binding (CREB) protein, but not NF-kB, by aspirin, the abrogation of aspirin-induced expression of CNTF by siRNA knockdown of CREB, the presence of a consensus CRE in the promoter of CNTF, and the recruitment of CREB and CREB-binding protein to the CNTF promoter by aspirin suggest that aspirin increases the expression of CNTF gene via the activation of CREB. Furthermore, we demonstrate that aspirin-induced astroglial CNTF was also functionally active and that supernatants of aspirin-treated astrocytes of wild type, but not CNTF null, mice increased myelin-associated proteins in oligodendrocytes and protected oligodendrocytes from TNF-a insult. These results highlight a new and novel myelinogenic property of aspirin, which may be of benefit for multiple sclerosis and other demyelinating disorders.
Hitting 'reset' in protein synthesis restores myelination: Suggests new treatment for misfolded protein diseases such as Alzheimer's
A potential new treatment strategy for patients with Charcot-Marie-Tooth disease is on the horizon, thanks to research by neuroscientists now at the University at Buffalo's Hunter James Kelly Research Institute and their colleagues in Italy and England.
New Technique For Making Myelinating Cells Holds Promise For The Treatment Of Multiple Sclerosis And Cerebral Palsy
MNT: This breakthrough now enables "on demand" production of myelinating cells, which provide a vital sheath of insulation that protects neurons and enables the delivery of brain impulses to the rest of the body. In patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced. "
A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination.
Differentiation of oligodendrocyte precursor cells (OPCs) is the most important event for the myelination of central nervous system (CNS) axons during development and remyelination in demyelinating diseases, while the underlying molecular mechanisms remain largely unknown. Here we show that NMDA receptor (NMDAR) is a functional regulator of OPCs differentiation and remyelination. First, GluN1, GluN2A, and GluN2B subunits are expressed in oligodendrocyte lineage cells (OLs) in vitro and in vivo by immunostaining and Western blot analysis. Second, in a purified rat OPC culture system, NMDARs specially mediate OPCs differentiation by enhancing myelin proteins expression and the processes branching at the immature to mature oligodendrocyte transition analyzed by a serial of developmental stage-specific antigens. Moreover, pharmacological NMDAR antagonists or specific knockdown of GluN1 by RNA interference in OPCs prevents the differentiation induced by NMDA. NMDA can activate the mammalian target of rapamycin (mTOR) signal in OPCs and the pro-differentiation effect of NMDA is obstructed by the mTOR inhibitor rapamycin, suggesting NMDAR exerts its effect through mTOR-dependent mechanism. Furthermore, NMDA increases numbers of myelin segments in DRG-OPC cocultures. Finally, NMDAR specific antagonist MK801 delays remyelination in the cuprizone model examined by LFB-PAS, immunofluorescence and electron microscopy. This effect appears to result from inhibiting OPCs differentiation as more NG2(+) OPCs but less GST-π(+) mature oligodendrocytes are observed. Together, these results indicate that NMDAR plays a critical role in the regulation of OPCs differentiation in vitro and remyelination in cuprizone model which may provide potential target for the treatment of demyelination disease.
The Antiaging Protein Klotho Enhances Oligodendrocyte Maturation and Myelination of the CNS
We have previously shown that myelin abnormalities characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates the development of aging-like phenotypes. Although the function of Klotho in brain is unknown, loss of Klotho expression leads to cognitive deficits. We found significant effects of Klotho on oligodendrocyte functions, including induced maturation of rat primary oligodendrocytic progenitor cells (OPCs) in vitro and myelination. Phosphoprotein analysis indicated that Klotho's downstream effects involve Akt and ERK signal pathways. Klotho increased OPC maturation, and inhibition of Akt or ERK function blocked this effect on OPCs. In vivo studies of Klotho knock-out mice and control littermates revealed that knock-out mice have a significant reduction in major myelin protein and gene expression. By immunohistochemistry, the number of total and mature oligodendrocytes was significantly lower in Klotho knock-out mice. Strikingly, at the ultrastructural level, Klotho knock-out mice exhibited significantly impaired myelination of the optic nerve and corpus callosum. These mice also displayed severe abnormalities at the nodes of Ranvier. To decipher the mechanisms by which Klotho affects oligodendrocytes, we used luciferase pathway reporters to identify the transcription factors involved. Together, these studies provide novel evidence for Klotho as a key player in myelin biology, which may thus be a useful therapeutic target in efforts to protect brain myelin against age-dependent changes and promote repair in multiple sclerosis.
Oligodendrocyte killing by quinolinic acid in vitro. (2001)
Quinolinic acid, which is produced by macrophages and microglia, can kill neurons in vivo and in vitro. To test whether quinolinic acid is toxic to oligodendrocytes, glial cells cultured from the brains of 2-day-old rats were incubated with quinolinic acid at concentrations known to kill neurons. The cells were then fixed and immunostained with MAbO4 to mark immature and mature oligodendrocytes and anti-myelin basic protein (MBP) to mark mature oligodendrocytes. The data indicated up to 54% reductions in the numbers of O4-positive cells in cultures after incubation with quinolinic acid. Apoptosis of O4-positive cells began during the first 6 h, and some of the apoptotic cells became fragmented. Further apoptosis, and clumping of dead MBP-positive oligodendrocytes, occurred during longer incubation with quinolinic acid. Thus, quinolinic acid arising from macrophages and microglia during autoimmune disease may take part in a mechanism of oligodendrocyte injury and killing.
Futurity.org – ‘Tube’ view of nerve fibers may monitor Multiple sclerosis
A new discovery could be a powerful tool for the diagnosis and monitoring of brain diseases like multiple sclerosis that have links to myelin loss.
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