Oligodendrocytes are highly specialized neural cells that produce myelin, essential for rapid electrical conduction of neural signals in the central nervous system (CNS). The emergence of oligodendrocytes and myelin was a critical step in the evolution of vertebrates, fundamental for the development of the mammalian connectome, and indispensable for miniaturization and enhanced computing power of the brain. The advance in cognitive capacity is paralleled by increasing eminence of white matter, composed of interconnected bundles of myelinated axons; white matter volume increases from 6% of the brain in shrews, considered related to the most primitive mammals, up to 50% in Homo sapiens. Myelinating oligodendrocytes together with smaller populations of oligodendrocyte precursor cells (OPCs) and satellite or perineuronal oligodendrocytes account for more than half of the glial cells in the human brain. Together, these three cell types make up the oligodendroglial cell lineage that express common lineage-specific proteins and transcription factors and display a degree of molecular and functional diversity. OPCs are the most numerous oligodendroglial cells during developmental axonal myelination, which extends postnatally for many years in humans. The generation of myelinating oligodendrocytes from OPCs throughout life continues to be important for adaptive plasticity of neural circuits and myelination of new axons required for learning. Myelination decreases in the aging brain and correlates with natural or physiological age-related cognitive decline. Like all neural cells, oligodendroglia express a wide assortment of ion channels, transporters, and neurotransmitter receptors that are essential for maintaining neuronal signaling, principally myelination, axonal metabolic support, and homeostatic regulation of the periaxonal microenvironment. Notably, OPCs are unique among neuroglia in that, like neurons, they are electrically excitable and form synapses with neurons. Oligodendroglial cells also contribute to neuroplasticity through multiple mechanisms including axon guidance, synapse formation, and adaptive myelination. In short, oligodendroglia are essential for normal CNS integrity, cognitive function, and behavior.

Oligodendroglia are the only cell lineage of the central nervous system (CNS) responsible for producing myelin. They originate from precursor cells known as oligodendrocyte precursor cells (OPCs), which are born around the ventricular zones of the brain and spinal cord and migrate throughout the developing CNS, and many of them ultimately differentiate into mature myelinating oligodendrocytes. Recent research has shown that OPCs and oligodendrocytes possess distinct characteristics when compared either to other types of glial cells in the CNS or to each other. Under different physiological and pathophysiological conditions, the processes of development or regeneration, the features, and, in some cases, even the functions of oligodendroglia can be modified. These changes can contribute to disease progression and affect the functional status of the nervous system. For instance, experience-dependent "adaptive" myelination plays a crucial role in the plasticity of neuronal circuits and influences learning processes; additionally, the non-myelinating functions of oligodendroglia expand their pathological potential, allowing them to regulate neuronal development and activity, angiogenesis, astrocyte maturation, and neuroinflammation. This chapter serves as a comprehensive introduction to oligodendroglia by presenting evidence from fundamental studies and fresh insights into their development, physiological and pathophysiological attributes, as well as the newly discovered non-myelinating functions.

The evolution of the nervous system emerged in primaeval animals to coordinate their behaviour then advanced by the division of function between neurones and neuroglia; neurones became dedicated to information processing and neuroglia specialised in homeostatic support. As the nervous system became more complex and neurones extended axonal connections, so periaxonal glial cells arose to provide axonal support. In many invertebrates, periaxonal glia produce multilamellar structures similar in architecture and function to the myelin sheath of vertebrates. These protomyelin structures support exceptionally high velocity of action potential propagation, which in some shrimps may reach 200 m/s. Myelin sheaths 'proper' are a vertebrate development and emerged in jawed fish with the central nervous system (CNS) of the brain and spinal cord becoming enclosed within the cranium and vertebral column. This was coincident with a clear division between oligodendrocytes that myelinate axons in the CNS and Schwann cells that myelinate peripheral axons; it seems likely that peripheral myelin evolved first. In the CNS, myelinated axons form the white matter, which interconnects the different regions of the CNS with each other and with the periphery. This is termed the connectome, which is particularly advanced in humans, occupying ~50% of total volume of the brain, compared to ~12% in rodents. The highly developed connectome, supported by oligodendroglial cells, is the foundation of human intelligence.

The central nervous system is susceptible to gradual decline with age, affecting all types of glial cells in the process. Compared to other glial cells, the oligodendroglial lineage is highly vulnerable to ageing and undergoes significant characteristic changes that impact upon its structure and impair its physiological functions. Therefore, the ageing and degeneration of oligodendroglia become major risk factors for neurodegenerative diseases. During the age-related disease process, changes in oligodendroglia lead to a decline in their ability to regenerate myelin and respond to the aged microenvironment, which are closely linked to the pathogenesis of neurodegenerative diseases, facilitating the emergence of these diseases in older populations. In this chapter, we introduce the physiological changes of oligodendroglia during ageing and the related mechanisms and then summarise their pathophysiological contributions to age-related cognitive disorders. Finally, we discuss potential therapeutic strategies that target oligodendroglia for future research on neurodegenerative diseases.

Myelinating oligodendrocytes and oligodendrocyte precursor cells (OPCs) make up half the cells in the central nervous system and are affected by and contribute to all neurological diseases. The pathology of myelinating oligodendrocytes is fundamentally characterized by myelin disruption and loss, termed demyelination, whereas that of OPCs is principally defined by remyelination and repair in the form of regeneration of myelinating oligodendrocytes. Demyelination is generally associated with white matter diseases, such as multiple sclerosis, although oligodendroglial pathology is a major factor in most neuropathologies, including Alzheimer's disease, ischaemic injury, and traumatic injury. Oligodendroglial changes are often driven by neuroinflammatory factors and involve oxidative stress, metabolic malfunction, and excitotoxicity. Understanding the complexities of demyelination and remyelination pathogenesis is essential for the development of new therapeutic strategies. In this chapter, we summarise the key features of demyelination and remyelination, discuss factors underlying a remyelination failure, and compare the differences between humans and mice. We propose some perspectives on treatment strategies for remyelination in the hope that future advances will provide solutions to the challenges associated with demyelinating diseases.

Oligodendrocytes are cells in the central nervous system that are specialised to form myelin sheaths around axons. They are generated from oligodendrocyte precursor cells that persist in the adult brain and are responsible for myelin plasticity that is essential for learning and repair in pathology. Oligodendrocytes exhibit morphological and molecular heterogeneity, and, besides their role in myelination, they provide metabolic and homeostatic support for neurones. In addition, some oligodendrocytes exhibit an immune function as antigen-presenting cells under certain conditions. The myelinating function of oligodendrocytes is essential for nervous system operational integrity, and the loss of myelin leads to neurodegeneration and an irreversible loss of function.

Leukodystrophies are a diverse group of inherited diseases characterised by white matter degenerative pathology. Leukodystrophies have a highly heterogeneous genetic background linked mainly to mutations in oligodendrocyte and astrocyte genes and, to lesser extent, microglia. The most prevalent leukodystrophies are caused by mutations in oligodendrocyte genes that encode the essential myelin proteins PLP1 and GalC in Pelizaeus-Merzbacher disease and Krabbe disease, respectively. Astrocyte leukodystrophies are led by Alexander disease, caused by mutations in the astrocyte gene GFAP. Vanishing white matter disease, the most prevalent inherited white matter pathology in children, is associated with astrocyte atrophy and cystic degeneration of the cerebral white matter. The pathogenic mechanisms in leukodystrophies depend on the genetic mutations and hence are extremely varied, but the diseases have in common white matter atrophy caused by the loss of oligodendrocytes and myelin, with or without marked reactive astrogliosis and microglia activation. The development of a range of animal models with the disruption of specific genes causing leukodystrophies and the use of pluripotent stem cells from people with different forms of leukodystrophy is advancing the understanding of the functional and cellular pathophysiology of these rare diseases.

Myelin is essential for superfast conduction of axons and underpins the massive computing power of the human brain. Myelinated axons form bundles of white matter to form the connectome which is one of the most prominent features of the human cerebral cortex. Myelin is produced by oligodendrocytes, which are the most numerous cells in white matter, together with oligodendrocyte precursor cells (OPC) that are responsible for life-long myelination. Myelin is essential for cognitive function and myelin plasticity is required for learning. It is noteworthy, therefore, that white matter shrinkage and myelin loss are hallmarks of natural ageing and are more severe in neuropathology, including multiple sclerosis and Alzheimer’s disease, as well as neuropsychiatric disorders such as schizophrenia. The precise age-related changes in oligodendroglial gene pathways at the transcriptome level identify the decline in oligodendrocyte regeneration as a key factor in white matter shrinkage in ageing. Keywords: oligodendrocyte; myelin; oligodendrocyte precursor cell; white matter; ageing; transcriptome

Background: Reactive astrogliosis and microgliosis are coordinated responses to CNS insults and are pathological hallmarks of traumatic brain injury (TBI). In these conditions, persistent reactive gliosis can impede tissue repopulation and limit neurogenesis. Thus, modulating this phenomenon has been increasingly recognized as potential therapeutic approach. Methods: In this study, we investigated the potential of the flavonoid agathisflavone to modulate astroglial and microglial injury responses and promote neurogenesis in the subventricular zone (SVZ) neurogenic niche. Agathisflavone, or the vehicle in controls, was administered directly into the lateral ventricles in postnatal day (P)8-10 mice by twice daily intracerebroventricular (ICV) injections for 3 days, and brains were examined at P11. Results: In the controls, ICV injection caused glial reactivity along the needle track, characterised immunohistochemically by increased astrocyte expression of glial fibrillary protein (GFAP) and the number of Iba-1+ microglia at the lesion site. Treatment with agathisflavone decreased GFAP expression, reduced both astrocyte reactivity and the number of Iba-1+ microglia at the core of the lesion site and the penumbra, and induced a 2-fold increase on the ratio of anti-inflammatory CD206+ to pro-inflammatory CD16/32+ microglia. Notably, agathisflavone increased the population of neuroblasts (GFAP+ type B cells) in all SVZ microdomains by up to double, without significantly increasing the number of neuronal progenitors (DCX+). Conclusions: Although future studies should investigate the underlying molecular mechanisms driving agathisflavone effects on microglial polarization and neurogenesis at different timepoints, these data indicate that agathisflavone could be a potential adjuvant treatment for TBI or central nervous system disorders that have reactive gliosis as a common feature.

MicroRNAs (miRs) act as important post-transcriptional regulators of gene expression in glial cells and have been shown to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Here, we investigated the effects of agathisflavone, a biflavonoid purified from the leaves of Cenostigma pyramidale (Tul.), on modulating the expression of miRs and inflammatory mediators in activated microglia. C20 human microglia were exposed to oligomers of the β-amyloid peptide (Aβ, 500 nM) for 4 h or to lipopolysaccharide (LPS, 1 µg/mL) for 24 h and then treated or not with agathisflavone (1 µM) for 24 h. We observed that β-amyloid and LPS activated microglia to an inflammatory state, with increased expression of miR-146a, miR-155, IL1-β, IL-6, and NOS2. Treatment with agathisflavone resulted in a significant reduction in miR146a and miR-155 induced by LPS or Aβ, as well as inflammatory cytokines IL1-β, IL-6, and NOS2. In cells stimulated with Aβ, there was an increase in p-STAT3 expression that was reduced by agathisflavone treatment. These data identify a role for miRs in the anti-inflammatory effect of agathisflavone on microglia in models of neuroinflammation and AD.

Coumarins are a class of biologically active natural products with a 1-benzopyran core skeleton found in roots, stems, seeds, bark, flowers, vegetables, and fruits of a large variety of plant families. A diverse panel of structural modifications lead to the formation of derivatives classified as simple, prenylated, geranylated, furano, pyrano, mono and sesquiterpenyl, and oligomeric coumarins, representing one of the most important classes and diversified natural products investigated in recent decades. Central nervous system (CNS) diseases are among the most serious faced by modern society and are characterized by neuronal cell loss in the brain and spinal cord leading to functional and sensory impairment. In particular, neurodegenerative diseases (NDD), such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, trauma, malignant tumors, and many other conditions, have become more common with aging of the population. In this chapter, we present the chemistry and the main knowledge about the targets and signaling of coumarins in preclinical in vitro and in vivo models of NDD and other CNS pathologies, highlighting the antiinflammatory, antioxidant, and antiapoptotic actions as the major neuroprotective mechanisms in this class of molecules.

Pathologies of the central nervous system (CNS) can be caused by toxic agents, traumatic damage, and can be triggered by neural degeneration related to aging or degenerative diseases, involving the accumulation of cytokines, neurotransmitters, and reactive radicals and irrespective of the etiology, involve reactive gliosis. In this context, neuroprotective strategies would be promising, not only to reduce the progression of neurodegeneration but also to recover the individual from the disease condition, and natural compounds with immunomodulatory potential may represent part of a new generation of bioactive drugs with pharmacological potential to protect and improve brain function in various neurodegenerative diseases. The consumption of flavonoids in the diet has been associated with reduced risk of neurodegenerative diseases (NDD) in humans, neuroprotection against relevant insults in animal models of study, as well as improvements in cognition and learning. Apigenin (4,5,7-trihydroxyflavone) is a flavonoid found in abundance in fruits such as oranges, chamomile, celery, parsley, red wine, onions, and especially in Passiflora flower. In this chapter, we present the main knowledge about the neuroprotective effects of apigenin in in vivo and in vitro models of NDD and other pathologies of the CNS, with a special focus on modulation of the glial neuroinflammatory response. Considering that apigenin has been presented neuroprotective, antiinflammatory, antioxidant, antiapoptotic, and immunomodulatory properties, it may constitute an alternative as a therapeutic agent for oxidative and inflammatory processes of the CNS.

Alterations in Dp71 expression, the most ubiquitous dystrophin isoform, have been associated with patient survival across tumours. Intriguingly, in certain malignancies, Dp71 acts as a tumour suppressor, while manifesting oncogenic properties in others. This diversity could be explained by the expression of two Dp71 splice variants encoding proteins with distinct C-termini, each with specific properties. Expression of these variants has impeded the exploration of their unique roles. Using CRISPR/Cas9, we ablated the Dp71f variant with the alternative C-terminus in a sarcoma cell line not expressing the canonical C-terminal variant, and conducted molecular (RNAseq) and functional characterisation of the knockout cells. Dp71f ablation induced major transcriptomic alterations, particularly affecting the expression of genes involved in calcium signalling and ECM-receptor interaction pathways. The genome-scale metabolic analysis identified significant downregulation of glucose transport via membrane vesicle reaction (GLCter) and downregulated glycolysis/gluconeogenesis pathway. Functionally, these molecular changes corresponded with, increased calcium responses, cell adhesion, proliferation, survival under serum starvation and chemotherapeutic resistance. Knockout cells showed reduced GLUT1 protein expression, survival without attachment and their migration and invasion in vitro and in vivo were unaltered, despite increased matrix metalloproteinases release. Our findings emphasise the importance of alternative splicing of dystrophin transcripts and underscore the role of the Dp71f variant, which appears to govern distinct cellular processes frequently dysregulated in tumour cells. The loss of this regulatory mechanism promotes sarcoma cell survival and treatment resistance. Thus, Dp71f is a target for future investigations exploring the intricate functions of specific DMD transcripts in physiology and across malignancies.

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.

Schizophrenia is a significant worldwide health concern, affecting over 20 million individuals and contributing to a potential reduction in life expectancy by up to 14.5 years. Despite its profound impact, the precise pathological mechanisms underlying schizophrenia continue to remain enigmatic, with previous research yielding diverse and occasionally conflicting findings. Nonetheless, one consistently observed phenomenon in brain imaging studies of schizophrenia patients is the disruption of white matter, the bundles of myelinated axons that provide connectivity and rapid signalling between brain regions. Myelin is produced by specialised glial cells known as oligodendrocytes, which have been shown to be disrupted in post-mortem analyses of schizophrenia patients. Oligodendrocytes are generated throughout life by a major population of oligodendrocyte progenitor cells (OPC), which are essential for white matter health and plasticity. Notably, a decline in a specific subpopulation of OPC has been identified as a principal factor in oligodendrocyte disruption and white matter loss in the aging brain, suggesting this may also be a factor in schizophrenia. In this review, we analysed genomic databases to pinpoint intersections between aging and schizophrenia and identify shared mechanisms of white matter disruption and cognitive dysfunction.

Astroglial cells are fundamental for the most basic functions of the central nervous system, which define its development, maintenance, survival and operation. Astroglia are the key element of the brain barriers, production and turnover of the cerebrospinal fluid, and ionostasis of the brain extracellular space. Astrocytes maintain the function of the glymphatic system responsible from the removal of cellular waste. Astrocytes are an indispensable part of the brain synaptic networks, controlling synaptogenesis, synaptic maintenance and synaptic elimination, through the astroglial synaptic cradle. Finally, astrocytic morphological and functional plasticity are critical elements for plastic remodelling of neuronal ensembles, this being critical for learning, memory and behaviour.

Astroglia are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defence of the central nervous system. Astroglia include several cell types, including numerous types of astrocytes, radial glia, ependymocytes and, in higher primates, specialised interlaminar astrocytes and astrocytes with varicose projections. Astroglial cells are highly heterogeneous in morphological appearance and physiological properties; they express a multitude of receptors, channels and membrane transporters. This extended complement of signalling and homeostatic molecules underlies the remarkable adaptive plasticity of astroglial cells and enables the functional maintenance of the CNS in development and ageing. Astroglia are fully integrated into neural networks and control homeostasis of the CNS at all levels of organisation from molecular to the whole organ.

Background Stroke is a leading cause of death and disability worldwide. A major factor in brain damage following ischemia is excitotoxicity caused by elevated levels of the neurotransmitter glutamate. In the brain, glutamate homeostasis is a primary function of astrocytes. Amburana cearensis has long been used in folk medicine and seed extract obtained with dichloromethane (EDAC) have previously been shown to exhibit cytoprotective activity in vitro. The aim of the present study was to analyse the activity of EDAC in hippocampal brain slices. Methods We prepared a dichloromethane extract (EDAC) from A. cearensis seeds and characterized the chemical constituents by 1H and 13C-NMR. Hippocampal slices from P6-8 or P90 Wistar rats were used for cell viability assay or glutamate uptake test. Hippocampal slices from P10-12 transgenic mice SOX10-EGFP and GFAP-EGFP and immunofluorescence for GS, GLAST and GLT1 were used to study oligodendrocytes and astrocytes. Results Astrocytes play a critical role in glutamate homeostasis and we provide immunohistochemical evidence that in excitotoxicity EDAC increased expression of glutamate transporters and glutamine synthetase, which is essential for detoxifying glutamate. Next, we directly examined astrocytes using transgenic mice in which glial fibrillary acidic protein (GFAP) drives expression of enhanced green fluorescence protein (EGFP) and show that glutamate excitotoxicity caused a decrease in GFAP-EGFP and that EDAC protected against this loss. This was examined further in the oxygen–glucose deprivation (OGD) model of ischemia, where EDAC caused an increase in astrocytic process branching, resulting in an increase in GFAP-EGFP. Using SOX10-EGFP reporter mice, we show that the acute response of oligodendrocytes to OGD in hippocampal slices is a marked loss of their processes and EDAC protected oligodendrocytes against this damage. Conclusion This study provides evidence that EDAC is cytoprotective against ischemia and glutamate excitotoxicity by modulating astrocyte responses and stimulating their glutamate homeostatic mechanisms.

>The need for new therapeutic approaches: Conventional drug discovery is a lengthy and expensive process, taking decades and billions of dollars to get a drug from bench to bedside. Much of the costs incurred are at the pre-clinical stages, between drug design and synthesis to delineating the cellular “Mechanisms of Action”(MoA). Notably, there is a very high risk of failure,