RESUMO
The emergence of myelinating oligodendrocytes represents a pivotal developmental milestone in vertebrates, given their capacity to ensheath axons and facilitate the swift conduction of action potentials. It is widely accepted that cortical oligodendrocyte progenitor cells (OPCs) arise from medial ganglionic eminence (MGE), lateral/caudal ganglionic eminence (LGE/CGE), and cortical radial glial cells (RGCs). Here, we used two different fate mapping strategies to challenge the established notion that the LGE generates cortical OPCs. Furthermore, we used a Cre/loxP-dependent exclusion strategy to reveal that the LGE/CGE does not give rise to cortical OPCs. Additionally, we showed that specifically eliminating MGE-derived OPCs leads to a significant reduction of cortical OPCs. Together, our findings indicate that the LGE does not generate cortical OPCs, contrary to previous beliefs. These findings provide a new view of the developmental origins of cortical OPCs and a valuable foundation for future research on both normal development and oligodendrocyte-related disease.
Assuntos
Córtex Cerebral , Oligodendroglia , Animais , Oligodendroglia/fisiologia , Oligodendroglia/citologia , Camundongos , Córtex Cerebral/embriologia , Córtex Cerebral/fisiologia , Córtex Cerebral/citologia , Células Precursoras de Oligodendrócitos/fisiologia , Células Precursoras de Oligodendrócitos/citologia , Diferenciação Celular , Eminência GanglionarRESUMO
Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10-8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Paralisia Supranuclear Progressiva , Proteínas tau , Humanos , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/metabolismo , Idoso , Masculino , Feminino , Proteínas tau/genética , Proteínas tau/metabolismo , Transcriptoma , Polimorfismo de Nucleotídeo Único , Neuroglia/metabolismo , Neuroglia/patologia , Idoso de 80 Anos ou mais , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Pessoa de Meia-Idade , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Estudos de Casos e Controles , Proteínas da MielinaRESUMO
Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory loss, cognitive decline, personality changes, and various neurological symptoms. The role of blood-brain barrier (BBB) injury, extracellular matrix (ECM) abnormalities, and oligodendrocytes (ODCs) dysfunction in AD has gained increasing attention, yet the detailed pathogenesis remains elusive. This study integrates single-cell sequencing of AD patients' cerebrovascular system with a genome-wide association analysis. It aims to elucidate the associations and potential mechanisms behind pericytes injury, ECM disorder, and ODCs dysfunction in AD pathogenesis. Finally, we identified that abnormalities in the pericyte PI3K-AKT-FOXO signaling pathway may be involved in the pathogenic process of AD. This comprehensive approach sheds new light on the complex etiology of AD and opens avenues for advanced research into its pathogenesis and therapeutic strategies.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Estudo de Associação Genômica Ampla , Pericitos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/etiologia , Humanos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Pericitos/patologia , Pericitos/metabolismo , Transdução de Sinais , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Matriz Extracelular/metabolismo , Microvasos/patologia , Microvasos/metabolismo , Análise de Célula Única , Feminino , Masculino , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
Multiple embryonic origins give rise to forebrain oligodendrocytes (OLs), yet controversies and uncertainty exist regarding their differential contributions. We established intersectional and subtractional strategies to genetically fate map OLs produced by medial ganglionic eminence/preoptic area (MGE/POA), lateral/caudal ganglionic eminences (LGE/CGE), and dorsal pallium in the mouse brain. We found that, contrary to the canonical view, LGE/CGE-derived OLs make minimum contributions to the neocortex and corpus callosum, but dominate piriform cortex and anterior commissure. Additionally, MGE/POA-derived OLs, instead of being entirely eliminated, make small but sustained contribution to cortex with a distribution pattern distinctive from those derived from the dorsal origin. Our study provides a revised and more comprehensive view of cortical and white matter OL origins, and established valuable new tools and strategies for future OL studies.
Assuntos
Oligodendroglia , Prosencéfalo , Animais , Oligodendroglia/metabolismo , Oligodendroglia/citologia , Prosencéfalo/embriologia , Prosencéfalo/citologia , Camundongos , Linhagem da Célula/genéticaRESUMO
Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.
Assuntos
MicroRNAs , Córtex Pré-Frontal , Comportamento Social , Isolamento Social , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos , Masculino , Córtex Pré-Frontal/metabolismo , Oligodendroglia/metabolismo , Camundongos Endogâmicos C57BL , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Comportamento Animal/fisiologia , Bainha de Mielina/metabolismo , Bainha de Mielina/genética , Ansiedade/genética , Ansiedade/metabolismo , FemininoRESUMO
Myelination of axons is a key determinant of fast action potential propagation, axonal health and circuit function. Previously considered a static structure, it is now clear that myelin is dynamically regulated in response to neuronal activity in the central nervous system (CNS). However, how activity-dependent signals are conveyed to oligodendrocytes remains unclear. Here, we review the potential mechanisms by which neurons could communicate changing activity levels to myelin, with a focus on the accumulating body of evidence to support activity-dependent vesicular signalling directly onto myelin sheaths. We discuss recent in vivo findings of activity-dependent fusion of neurotransmitter vesicles from non-synaptic axonal sites, and how modulation of this vesicular fusion regulates the stability and growth of myelin sheaths. We also consider the potential mechanisms by which myelin could sense and respond to axon-derived signals to initiate remodelling, and the relevance of these adaptations for circuit function. We propose that axonal vesicular signalling represents an important and underappreciated mode of communication by which neurons can transmit activity-regulated signals to myelinating oligodendrocytes and, potentially, more broadly to other cell types in the CNS.
Assuntos
Axônios , Bainha de Mielina , Neurotransmissores , Bainha de Mielina/metabolismo , Axônios/metabolismo , Animais , Humanos , Neurotransmissores/metabolismo , Transmissão Sináptica , Oligodendroglia/metabolismo , Transdução de Sinais , Vesículas Sinápticas/metabolismo , Neurônios/metabolismoRESUMO
The corpus callosum, a major white matter tract in the brain, undergoes age-related functional changes. To extend our investigation of age-related gene expression dynamics in the mouse corpus callosum, we compared RNA-seq data from 2 week-old and 12 week-old wild-type C57BL/6 J mice and identified the differentially expressed genes (e.g., Marcksl1, Chst3, C4b, Neat1, Ndrg1, Emid1, etc.) between these ages. Interestingly, we found that genes highly expressed in myelinating oligodendrocytes were upregulated in 12 week-old mice compared to 2 week-old mice, while genes highly expressed in oligodendrocyte precursor cells (OPCs) and newly formed oligodendrocytes were downregulated. Furthermore, by comparing these genes with the datasets from 20 week-old and 96 week-old mice, we identified novel sets of genes with age-dependent variations in the corpus callosum. These gene expression changes potentially affect key biological pathways and may be closely linked to age-related neurological disorders, including dementia and stroke. Therefore, our results provide an additional dataset to explore age-dependent gene expression dynamics of oligodendrocyte lineage cells in the corpus callosum.
Assuntos
Linhagem da Célula , Corpo Caloso , Camundongos Endogâmicos C57BL , Oligodendroglia , Transcriptoma , Animais , Corpo Caloso/metabolismo , Corpo Caloso/citologia , Camundongos , Oligodendroglia/metabolismo , Oligodendroglia/citologia , Linhagem da Célula/genética , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/citologia , Envelhecimento/genética , Perfilação da Expressão Gênica , Masculino , Fatores EtáriosRESUMO
Several neurodegenerative diseases, such as multiple sclerosis and Parkinson's disease, are linked to alterations in myelin content or structure. Transmembrane receptors such as integrins could be involved in these alterations. In the present study, we investigated the role of αv-integrins in experimental models of neuroinflammation and demyelination with the use of lebecetin (LCT), a C-lectin protein purified from Macrovipera lebetina viper venom, as an αv-integrin modulator. In a model of neuroinflammation, LCT inhibited the upregulation of αv, ß3, ß5, α5, and ß1 integrins, as well as the associated release of pro-inflammatory factor IL-6 and chemokine CXCL-10, and decreased the expression of phosphorylated NfκB. The subsequent "indirect culture" between reactive astrocytes and oligodendrocytes showed a down-regulation of αv and ß3 integrins versus upregulation of ß1 one, accompanied by a reduced expression of myelin basic protein (MBP). Treatment of oligodendrocytes with LCT rectified the changes in integrin and MBP expression. Through Western blot quantification, LCT was shown to upregulate the expression levels of PI3K and p-mTOR while downregulating expression levels of p-AKT in oligodendrocytes, suggesting the neuroprotective and pro-myelinating effects of LCT may be related to the PI3K/mTor/AKT pathway. Concomitantly, we found that LCT promoted remyelination by tracking the increased expression of MBP in the brains of cuprizone-intoxicated mice. These results point to an involvement of integrins in not only neuroinflammation but demyelination as well. Thus, targeting αv integrins could offer potential therapeutic avenues for the treatment of demyelinating diseases.
Assuntos
Doenças Desmielinizantes , Modelos Animais de Doenças , Doenças Neuroinflamatórias , Venenos de Víboras , Animais , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/induzido quimicamente , Venenos de Víboras/farmacologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Integrina alfaV/metabolismo , Camundongos , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , MasculinoRESUMO
BACKGROUND: Melatonin has been shown to be neuroprotective in different animal models of neonatal hypoxic-ischemic brain injury. However, its exact molecular mechanism of action remains unknown. Our aim was to prove melatonin's short- and long-term neuroprotection and investigate its role on the AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway following neonatal hypoxic-ischemic brain injury. METHODS AND RESULTS: Seven-day-old Wistar rat pups were exposed to hypoxia-ischemia, followed by melatonin or vehicle treatment. Detailed analysis of the AMPK/mTOR/autophagy pathway, short- and long-term neuroprotection, myelination, and oligodendrogenesis was performed at different time points. At 7 days after hypoxia-ischemia, melatonin-treated animals showed a significant decrease in tissue loss, increased oligodendrogenesis, and myelination. Long-term neurobehavioral results showed significant motor improvement following melatonin treatment. Molecular pathway analysis showed a decrease in the AMPK expression, with a significant increase at mTOR's downstream substrates, and a significant decrease at the autophagy marker levels in the melatonin group compared with the vehicle group. CONCLUSIONS: Melatonin treatment reduced brain area loss and promoted oligodendrogenesis with a clear improvement of motor function. We found that melatonin associated neuroprotection is regulated via the AMPK/mTOR/autophagy pathway. Considering the beneficial effects of melatonin and the results of our study, melatonin seems to be an optimal candidate for the treatment of newborns with hypoxic-ischemic brain injury in high- as well as in low- and middle-income countries.
Assuntos
Proteínas Quinases Ativadas por AMP , Animais Recém-Nascidos , Autofagia , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica , Melatonina , Fármacos Neuroprotetores , Ratos Wistar , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Melatonina/farmacologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/patologia , Serina-Treonina Quinases TOR/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Ratos , Comportamento Animal/efeitos dos fármacosRESUMO
Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.
Assuntos
Astrócitos , Clusterina , Doenças Desmielinizantes , Modelos Animais de Doenças , Remielinização , Animais , Feminino , Humanos , Camundongos , Apoptose/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Clusterina/metabolismo , Clusterina/genética , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Remielinização/efeitos dos fármacos , Transdução de SinaisRESUMO
Even though several highly effective treatments have been developed for multiple sclerosis (MS), the underlying pathological mechanisms and drivers of the disease have not been fully elucidated. In recent years, there has been a growing interest in studying neuroinflammation in the context of glial cell involvement as there is increasing evidence of their central role in disease progression. Although glial cell communication and proper function underlies brain homeostasis and maintenance, their multiple effects in an MS brain remain complex and controversial. In this review, we aim to provide an overview of the contribution of glial cells, oligodendrocytes, astrocytes, and microglia in the pathology of MS during both the activation and orchestration of inflammatory mechanisms, as well as of their synergistic effects during the repair and restoration of function. Additionally, we discuss how the understanding of glial cell involvement in MS may provide new therapeutic targets either to limit disease progression or to facilitate repair.
Assuntos
Esclerose Múltipla , Neuroglia , Doenças Neuroinflamatórias , Humanos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Animais , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Microglia/metabolismo , Microglia/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Encéfalo/metabolismo , Encéfalo/patologiaRESUMO
Our understanding of Alzheimer's disease (AD) has evolved from focusing solely on neurons to recognizing the role of glia. A recent study in PLOS Biology revealed that oligodendrocytes are an important source of Aß that impairs neuronal function.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Oligodendroglia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Oligodendroglia/metabolismo , Oligodendroglia/fisiologia , Oligodendroglia/patologia , Humanos , Peptídeos beta-Amiloides/metabolismo , Animais , Neurônios/metabolismo , Neurônios/fisiologiaRESUMO
Malformation of cortical development is an important cause of drug-resistant epilepsy in young children. Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) has been added to the last focal cortical dysplasia (FCD) classification and commonly involves the frontal lobe. The semiology at the onset of epilepsy is dominated by non-lateralizing infantile spasm; the boundaries of the malformation are usually difficult to determine by magnetic resonance imaging (MRI) and positron emission tomography (PET), and electroencephalography (EEG) findings are often widespread. Therefore, the traditional concept and strategy of preoperative evaluation to determine the extent of the epileptogenic zone by comprehensive anatomo-electro-clinical methods are difficult to implement. Frontal disconnection is an effective surgical method for the treatment of epilepsy, but there are few related reports. A total of 8 children with histo-pathologically confirmed MOGHE were retrospectively studied. MOGHE was located in the frontal lobe in all patients, and frontal disconnection was performed. The periinsular approach was used in the disconnective procedures, divided into several surgical steps: the partial inferior frontal gyrus resection, the frontobasal and intrafrontal disconnection, and the anterior corpus callosotomy. One patient presented with a short-term postoperative speech disorder, while another patient exhibited transient postoperative limb weakness. No long-term postoperative complications were observed. At 2 years after surgery, 75% of patients were seizure-free, with cognitive improvement in half of them. This finding suggested that frontal disconnection is an effective and safe surgical procedure for the treatment of MOGHE instead of extensive resection in the frontal lobe.
Assuntos
Lobo Frontal , Malformações do Desenvolvimento Cortical , Humanos , Lobo Frontal/cirurgia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Malformações do Desenvolvimento Cortical/cirurgia , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/patologia , Masculino , Feminino , Pré-Escolar , Criança , Epilepsia/cirurgia , Epilepsia/diagnóstico por imagem , Epilepsia/etiologia , Oligodendroglia/patologia , Lactente , Estudos Retrospectivos , Epilepsia do Lobo Frontal/cirurgia , Epilepsia do Lobo Frontal/diagnóstico por imagem , Epilepsia do Lobo Frontal/patologia , Hiperplasia/cirurgiaRESUMO
BACKGROUND: Preterm birth is associated with brain injury and long-term behavioral abnormalities, for which there are limited prevention options. When born preterm, infants prematurely lose placental neurosteroid (allopregnanolone) support. This increases the risk of excitotoxic damage to the brain, which increases the risk of injury, causing long-term deficits in behavior, myelination, and alterations to neurotransmitter pathways. We propose that postnatal restoration of neurosteroid action through zuranolone therapy will reduce neurological impairments following preterm birth. METHODS: Guinea pig dams underwent survival cesarean section surgery to deliver pups prematurely (GA64) or at term (GA69). Between birth and term equivalence age, preterm pups received vehicle (15% ß-cyclodextrin) or the allopregnanolone analogue zuranolone (1 mg/kg/day). Behavioral analysis was performed at postnatal day (PND) 7 and 40, before tissue collection at PND 42. Immunostaining for myelin basic protein (MBP), as well as real-time polymerase chain reaction to characterize oligodendrocyte lineage and neurotransmitter pathways, was performed in frontal cortex tissues. RESULTS: Zuranolone treatment prevented the hyperactive phenotype in preterm-born offspring, most markedly in males. Additionally, preterm-related reductions in MBP were ameliorated. Several preterm-related alterations in mRNA expression of dopaminergic, glutamatergic, and GABAergic pathways were also restored back to that of a term control level. CONCLUSION: This is the first study to assess zuranolone treatment as a neuroprotective therapy following preterm birth. Zuranolone treatment improved behavioral outcomes and structural changes in the preterm offspring, which continued long term until at least a late childhood timepoint. Clinical studies are warranted for further exploring the neuroprotective possibilities of this treatment following preterm birth.
Assuntos
Lobo Frontal , Pregnanolona , Nascimento Prematuro , Animais , Pregnanolona/farmacologia , Feminino , Cobaias , Masculino , Nascimento Prematuro/prevenção & controle , Nascimento Prematuro/tratamento farmacológico , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Animais Recém-Nascidos , Gravidez , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Proteína Básica da Mielina/metabolismoRESUMO
CNS diseases associated with compromised blood supply and/or vascular integrity are one of the leading causes of mortality and disability in adults worldwide and are also among 10 most common causes of death in children. Angiogenesis is an essential element of regeneration processes upon nervous tissue damage and can play a crucial role in neuroprotection. Here we review the features of cerebral vascular regeneration after ischemic stroke, including the complex interactions between endothelial cells and other brain cell types (neural stem cells, astrocytes, microglia, and oligodendrocytes). The mechanisms of reciprocal influence of angiogenesis and neurogenesis, the role of astrocytes in the formation of the blood-brain barrier, and roles of microglia and oligodendrocytes in vascular regeneration are discussed. Understanding the mechanisms of angiogenesis regulation in CNS is of critical importance for the development of new treatments of neurovascular pathologies.
Assuntos
Astrócitos , Barreira Hematoencefálica , AVC Isquêmico , Neovascularização Fisiológica , Células-Tronco Neurais , Neurogênese , Humanos , AVC Isquêmico/fisiopatologia , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Neovascularização Fisiológica/fisiologia , Neurogênese/fisiologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/fisiologia , Células-Tronco Neurais/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Oligodendroglia/fisiologia , Microglia/patologia , Microglia/metabolismo , Microglia/fisiologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Sistema Nervoso Central/irrigação sanguínea , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , AngiogêneseRESUMO
Agathisflavone is a flavonoid that exhibits anti-inflammatory and anti-oxidative properties. Here, we investigated the neuroprotective effects of agathisflavone on central nervous system (CNS) neurons and glia in the cerebellar slice ex vivo model of neonatal ischemia. Cerebellar slices from neonatal mice, in which glial fibrillary acidic protein (GFAP) and SOX10 drive expression of enhanced green fluorescent protein (EGFP), were used to identify astrocytes and oligodendrocytes, respectively. Agathisflavone (10 µM) was administered preventively for 60 min before inducing ischemia by oxygen and glucose deprivation (OGD) for 60 min and compared to controls maintained in normal oxygen and glucose (OGN). The density of SOX-10+ oligodendrocyte lineage cells and NG2 immunopositive oligodendrocyte progenitor cells (OPCs) were not altered in OGD, but it resulted in significant oligodendroglial cell atrophy marked by the retraction of their processes, and this was prevented by agathisflavone. OGD caused marked axonal demyelination, determined by myelin basic protein (MBP) and neurofilament (NF70) immunofluorescence, and this was blocked by agathisflavone preventative treatment. OGD also resulted in astrocyte reactivity, exhibited by increased GFAP-EGFP fluorescence and decreased expression of glutamate synthetase (GS), and this was prevented by agathisflavone pretreatment. In addition, agathisflavone protected Purkinje neurons from ischemic damage, assessed by calbindin (CB) immunofluorescence. The results demonstrate that agathisflavone protects neuronal and myelin integrity in ischemia, which is associated with the modulation of glial responses in the face of ischemic damage.
Assuntos
Animais Recém-Nascidos , Cerebelo , Flavonoides , Fármacos Neuroprotetores , Animais , Fármacos Neuroprotetores/farmacologia , Camundongos , Cerebelo/metabolismo , Cerebelo/efeitos dos fármacos , Flavonoides/farmacologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Glucose/metabolismo , BiflavonoidesRESUMO
Schizophrenic individuals display disrupted myelination patterns, altered oligodendrocyte distribution, and abnormal oligodendrocyte morphology. Schizophrenia is linked with dysregulation of a variety of genes involved in oligodendrocyte function and myelin production. Single-nucleotide polymorphisms (SNPs) and rare mutations in myelination-related genes are observed in certain schizophrenic populations, representing potential genetic risk factors. Downregulation of myelination-related RNAs and proteins, particularly in frontal and limbic regions, is consistently associated with the disorder across multiple studies. These findings support the notion that disruptions in myelination may contribute to the cognitive and behavioral impairments experienced in schizophrenia, although further evidence of causation is needed.
Assuntos
Bainha de Mielina , Esquizofrenia , Esquizofrenia/genética , Esquizofrenia/patologia , Esquizofrenia/metabolismo , Humanos , Bainha de Mielina/genética , Bainha de Mielina/patologia , Bainha de Mielina/metabolismo , Animais , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Polimorfismo de Nucleotídeo Único/genética , Proteínas da Mielina/genéticaRESUMO
Myelin is an insulator that forms around axons that enhance the conduction velocity of nerve fibers. Oligodendrocytes dramatically change cell morphology to produce myelin throughout the central nervous system (CNS). Cytoskeletal alterations are critical for the morphogenesis of oligodendrocytes, and actin is involved in cell differentiation and myelin wrapping via polymerization and depolymerization, respectively. Various protein members of the myosin superfamily are known to be major binding partners of actin filaments and have been intensively researched because of their involvement in various cellular functions, including differentiation, cell movement, membrane trafficking, organelle transport, signal transduction, and morphogenesis. Some members of the myosin superfamily have been found to play important roles in the differentiation of oligodendrocytes and in CNS myelination. Interestingly, each member of the myosin superfamily expressed in oligodendrocyte lineage cells also shows specific spatial and temporal expression patterns and different distributions. In this review, we summarize previous findings related to the myosin superfamily and discuss how these molecules contribute to myelin formation and regeneration by oligodendrocytes.
Assuntos
Bainha de Mielina , Miosinas , Oligodendroglia , Animais , Humanos , Bainha de Mielina/metabolismo , Bainha de Mielina/fisiologia , Miosinas/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/fisiologia , Regeneração Nervosa/fisiologia , Diferenciação Celular/fisiologiaRESUMO
Developmental myelination is a protracted process in the mammalian brain1. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age2-4. We tested this theory in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity5. During adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. To determine whether oligodendrocyte maturation in turn regulates neuronal plasticity, we genetically blocked oligodendrocyte differentiation and myelination in adolescent mice. In adult mice lacking adolescent oligodendrogenesis, a brief period of monocular deprivation led to a significant decrease in visual cortex responses to the deprived eye, reminiscent of the plasticity normally restricted to adolescence. This enhanced functional plasticity was accompanied by a greater turnover of dendritic spines and coordinated reductions in spine size following deprivation. Furthermore, inhibitory synaptic transmission, which gates experience-dependent plasticity at the circuit level, was diminished in the absence of adolescent oligodendrogenesis. These results establish a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of developmental myelination acting as a functional brake on neuronal plasticity.
Assuntos
Espinhas Dendríticas , Bainha de Mielina , Plasticidade Neuronal , Oligodendroglia , Córtex Visual , Animais , Plasticidade Neuronal/fisiologia , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Oligodendroglia/fisiologia , Córtex Visual/citologia , Córtex Visual/fisiologia , Córtex Visual/crescimento & desenvolvimento , Camundongos , Bainha de Mielina/metabolismo , Masculino , Espinhas Dendríticas/fisiologia , Espinhas Dendríticas/metabolismo , Feminino , Transmissão Sináptica/fisiologia , Privação Sensorial/fisiologia , Diferenciação Celular , Visão Monocular/fisiologia , Camundongos Endogâmicos C57BLRESUMO
Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein an H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased the expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination.