Synaptotagmin 4 Supports Spontaneous Axon Sprouting after Spinal Cord Injury.

Injuries to the central nervous system (CNS) can cause severe neurological deficits. Axonal regrowth is a fundamental process for the reconstruction of compensatory neuronal networks after injury; however, it is extremely limited in the adult mammalian CNS. In this study, we conducted a loss-of-function genetic screen in cortical neurons, combined with a Web resource-based phenotypic screen, and identified synaptotagmin 4 (Syt4) as a novel regulator of axon elongation. Silencing Syt4 in primary cultured cortical neurons inhibits neurite elongation, with changes in gene expression involved in signaling pathways related to neuronal development. In a spinal cord injury model, inhibition of Syt4 expression in cortical neurons prevented axonal sprouting of the corticospinal tract, as well as neurological recovery after injury. These results provide a novel therapeutic approach to CNS injury by modulating Syt4 function.

Expression and distribution of hypoxia-inducible factor-1α and vascular endothelial growth factor in comparison between radiation necrosis and tumor tissue in metastatic brain tumor: A case report.

We report the case of a 70-year-old woman with metastatic brain tumors who underwent surgical removal of the tumor and radiation necrosis. The patient had a history of colon cancer and had undergone surgical removal of a left occipital tumor. Histopathological evaluation revealed a metastatic brain tumor. The tumor recurred six months after surgical removal, followed by whole-brain radiotherapy, and the patient underwent stereotactic radiosurgery. Six months later, the perifocal edema had increased, and the patient became symptomatic. The diagnosis was radiation necrosis and corticosteroids were initially effective. However, radiation necrosis became uncontrollable, and the patient underwent removal of necrotic tissue two years after stereotactic radiosurgery. Pathological findings predominantly showed necrotic tissue with some tumor cells. Since the vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) were expressed around the necrotic tissue, the main cause of the edema was determined as radiation necrosis. Differences in the expression levels and distribution of HIF-1α and VEGF were observed between treatment-naïve and recurrent tumor tissue and radiation necrosis. This difference suggests the possibility of different mechanisms for edema formation due to the tumor itself and radiation necrosis. Although distinguishing radiation necrosis from recurrent tumors using MRI remains challenging, the pathophysiological mechanism of perifocal edema might be crucial for differentiating radiation necrosis from recurrent tumors.

Free fatty acids support oligodendrocyte survival in a mouse model of amyotrophic lateral sclerosis.

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the white matter degeneration. Although changes in blood lipids are involved in the pathogenesis of neurological diseases, the pathological role of blood lipids in ALS remains unclear. Methods and results: We performed lipidome analysis on the plasma of ALS model mice, mutant superoxide dismutase 1 (SOD1G93A) mice, and found that the concentration of free fatty acids (FFAs), including oleic acid (OA) and linoleic acid (LA), decreased prior to disease onset. An in vitro study revealed that OA and LA directly inhibited glutamate-induced oligodendrocytes cell death via free fatty acid receptor 1 (FFAR1). A cocktail containing OA/LA suppressed oligodendrocyte cell death in the spinal cord of SOD1G93A mice. Discussion: These results suggested that the reduction of FFAs in the plasma is a pathogenic biomarker for ALS in the early stages, and supplying a deficiency in FFAs is a potential therapeutic approach for ALS by preventing oligodendrocyte cell death.

Lysophosphatidic acid stimulates pericyte migration via LPA receptor 1.

Lysophosphatidic acid (LPA) is a bioactive compound known to regulate various vascular functions. However, despite the fact that many vascular functions are regulated by peri-vascular cells such as pericytes, the effect of LPA on brain pericytes has not been fully evaluated. Thus, we designed this study to evaluate the effects of LPA on brain pericytes. These experiments revealed that while LPA receptors (LPARs) are expressed in cultured pericytes from mouse brains, LPA treatment does not influence the proliferation of these cells but does have a profound impact on their migration, which is regulated via the expression of LPAR1. LPAR1 expression was also detected in human pericyte culture and LPA treatment of these cells also induced migration. Taken together these findings imply that LPA-LPAR1 signaling is one of the key mechanisms modulating pericyte migration, which may help to control vascular function during development and repair processes.

Circulating factors that influence the central nervous system remyelination.

Injury in the central nervous system leads to neurological deficits, depending on the disruption of neural networks. Remyelination, which occurs partially and spontaneously, is a critical process in the regeneration of neural networks to recover from neurological deficits. Remyelination depends on the development of oligodendrocytes, including the proliferation of oligodendrocyte precursor cells (OPCs) and the differentiation of OPCs into mature oligodendrocytes to form myelin. OPC proliferation and differentiation are regulated by intracellular and extracellular mechanisms, and recent studies have demonstrated that circulating factors secreted from peripheral organs or infiltrated immune cells play a key role in controlling oligodendrocyte development following remyelination in adult mammals. In this review, we describe the beneficial and detrimental effects of systemic environments, such as circulating factors derived from peripheral organs and immune cells, on CNS remyelination.

Microglial ASD-related genes are involved in oligodendrocyte differentiation.

Autism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNA-binding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc2). Although these ASD-related genes are detected in glial cells such as microglia, the effect of Chd8 or Tsc2 deficiency on microglial functions and microglia-mediated brain development remains unclear. In this study, we investigated the role of microglial Chd8 and Tsc2 in cytokine expression, phagocytosis activity, and neuro/gliogenesis from neural stem cells (NSCs) in vitro. Chd8 or Tsc2 knockdown in microglia reduced insulin-like growth factor-1(Igf1) expression under lipopolysaccharide (LPS) stimulation. In addition, phagocytosis activity was inhibited by Tsc2 deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd8 or Tsc2 deficiency. These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD.

Interleukin-17A regulates ependymal cell proliferation and functional recovery after spinal cord injury in mice.

Ependymal cells have been suggested to act as neural stem cells and exert beneficial effects after spinal cord injury (SCI). However, the molecular mechanism underlying ependymal cell regulation after SCI remains unknown. To examine the possible effect of IL-17A on ependymal cell proliferation after SCI, we locally administrated IL-17A neutralizing antibody to the injured spinal cord of a contusion SCI mouse model, and revealed that IL-17A neutralization promoted ependymal cell proliferation, which was paralleled by functional recovery and axonal reorganization of both the corticospinal tract and the raphespinal tract. Further, to test whether ependymal cell-specific manipulation of IL-17A signaling is enough to affect the outcomes of SCI, we generated ependymal cell-specific conditional IL-17RA-knockout mice and analyzed their anatomical and functional response to SCI. As a result, conditional knockout of IL-17RA in ependymal cells enhanced both axonal growth and functional recovery, accompanied by an increase in mRNA expression of neurotrophic factors. Thus, Ependymal cells may enhance the regenerative process partially by secreting neurotrophic factors, and IL-17A stimulation negatively regulates this beneficial effect. Molecular manipulation of ependymal cells might be a viable strategy for improving functional recovery.

Dimethylarginine dimethylaminohydrolase 1 as a novel regulator of oligodendrocyte differentiation in the central nervous system remyelination.

Remyelination is a regenerative process that restores the lost neurological function and partially depends on oligodendrocyte differentiation. Differentiation of oligodendrocytes spontaneously occurs after demyelination, depending on the cell intrinsic mechanisms. By combining a loss-of-function genomic screen with a web-resource-based candidate gene identification approach, we identified that dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a novel regulator of oligodendrocyte differentiation. Silencing DDAH1 in oligodendrocytes prevented the expression of myelin basic protein in mouse oligodendrocyte culture with the change in expression of genes annotated with oligodendrocyte development. DDAH1 inhibition attenuated spontaneous remyelination in a cuprizone-induced demyelinated mouse model. Conversely, increased DDAH1 expression enhanced remyelination capacity in experimental autoimmune encephalomyelitis. These results provide a novel therapeutic option for demyelinating diseases by modulating DDAH1 activity.

[Molecular mechanism of brain development and neurodevelopmental disorders regulated be neuroimmune system].

Recent studies have revealed that neuroimmune system is involved in the brain development and the pathogenesis of neurological diseases. However, it remains unclear how neuroimmune system modulates brain functions at a molecular level. We identified the role of immune cells in brain development and inflammatory neurological diseases. We demonstrated that B cells were abundant in the developing brain, and contribute to myelination by promoting the proliferation of oligodendrocyte precursor cells. In other study, we identified the role of microglia, which are immune cells in central nervous system, in the progression of autoimmune encephalomyelitis. We depleted microglia by PLX3397, an inhibitor of colony-stimulating factor receptor 1 (CSF-1R), in autoimmune encephalomyelitis, and showed that microglia regulate the T cell proliferation and differentiation during disease progression. In this article, we introduce the recent findings of the role of neuroimmune system in the brain development and pathogenesis of neurological diseases.

Age-dependent decline in remyelination capacity is mediated by apelin-APJ signaling.

Age-related regeneration failure in the central nervous system can occur as a result of a decline in remyelination efficacy. The responsiveness of myelin-forming cells to signals for remyelination is affected by aging-related epigenetic modification; however, the molecular mechanism is not fully clarified. In the present study, we report that the apelin receptor (APJ) mediates remyelination efficiency with age. APJ expression in myelin-forming cells is correlated with age-associated changes in remyelination efficiency, and the activation of APJ promotes remyelination through the translocation of myelin regulatory factor. APJ signaling activation promoted remyelination in both aged mice with toxin-induced demyelination and mice with experimental autoimmune encephalomyelitis. In human cells, APJ activation enhanced the expression of remyelination markers. Impaired oligodendrocyte function in aged animals can be reversibly reactivated; thus, the results demonstrate that dysfunction of the apelin-APJ system mediates remyelination failure in aged animals, and that their myelinating function can be reactivated by APJ activation.

Function of Lymphocytes in Oligodendrocyte Development.

Oligodendrocytes generate myelin sheaths to promote rapid neurotransmission in the central nervous system (CNS). During brain development, oligodendrocyte precursor cells (OPCs) are generated in the medial ganglionic eminence, lateral ganglionic eminence, and dorsal pallium. OPCs proliferate and migrate throughout the CNS at the embryonic stage. After birth, OPCs differentiate into mature oligodendrocytes, which then insulate axons. Oligodendrocyte development is regulated by the extrinsic environment including neurons, astrocytes, and immune cells. During brain development, B lymphocytes are present in the meningeal space, and are involved in oligodendrocyte development by promoting OPC proliferation. T lymphocytes mediate oligodendrocyte development during the remyelination process. Moreover, a subset of microglia contributes to oligodendrocyte development during the neonatal periods. Therefore, the immune system, especially lymphocytes and microglia, contribute to oligodendrocyte development during brain development and remyelination.

A novel protocol for three-dimensional rotational venography with low-dose contrast media in preoperative angiography of brain tumours.

AIM: The most appropriate imaging protocol for three-dimensional rotational venography (3D RV) has not been established. The aim of this study was to optimise the protocol for 3D RV with low-dose contrast media using time-density curve analysis. METHODS: Twenty-five consecutive patients with brain tumours who received preoperative assessment with 3D RV were retrospectively collected and included in this study. To optimise the imaging delay time of 3D RV with low-dose contrast media, time-density curve analysis was performed on two-dimensional conventional angiography. The image quality for depicting cortical veins and venous sinuses was compared to that of magnetic resonance (MR) venography in five cases. RESULTS: A total of 27 3D RVs were performed in 25 patients. The time-density curves of cortical veins were different from those of cerebral arteries or sinuses. The mean time to peak of cortical veins was significantly longer than the time to peak of cerebral arteries (2.47 ± 0.35 seconds vs. 6.44 ± 1.14 seconds; p < 0.0001) and shorter than the time to peak of venous sinuses (6.44 ± 1.14 seconds vs. 8.18 ± 1.12 seconds; p < 0.0001). The optimal imaging delay time could be determined as the phases in which cortical arterial opacities disappeared and cortical veins started to appear. The mean dose of injected contrast media was 5.3 mL. The image quality of cortical veins in 3D RV was superior to that in MR venography in all cases. CONCLUSIONS: Three-dimensional RV with low-dose contrast media was useful for the preoperative assessment of cortical veins in patients with brain tumours.

Microglia suppress the secondary progression of autoimmune encephalomyelitis.

Secondary progressive multiple sclerosis (SPMS) is an autoimmune disease of the central nervous system (CNS) characterized by progressive motor dysfunction, sensory deficits, and visual problems. The pathological mechanism of SPMS remains poorly understood. In this study, we investigated the role of microglia, immune cells in the CNS, in a secondary progressive form of experimental autoimmune encephalomyelitis (EAE), the mouse model of SPMS. We induced EAE in nonobese diabetic mice and treated the EAE mice with PLX3397, an antagonist of colony stimulating factor-1 receptor, during secondary progression in order to deplete microglia. The results showed that PLX3397 treatment significantly exacerbated secondary progression of EAE and increased mortality rates. Additionally, histological analysis showed that PLX3397 treatment significantly promoted inflammation, demyelination, and axonal degeneration. Moreover, the number of CD4+ T cells in the spinal cord of EAE mice was expanded due to PLX3397-mediated proliferation. These results suggest that microglia suppressed secondary progression of EAE by inhibiting the proliferation of CD4+ T cells in the CNS.

Microglia promote the proliferation of neural precursor cells by secreting osteopontin.

Microglia are central nervous system-resident immune cells that play a crucial role in brain development by interacting with neural precursor cells (NPCs). It has been reported that microglia regulate the number of NPC by phagocytosis, inducing apoptosis, and promoting proliferation. Microglia surrounding the subventricular zone express osteopontin (OPN) during brain development. The present study investigated the role of microglia in proliferation of NPCs in vitro, and identified the OPN receptor critical for proliferation of NPCs. Microglia co-cultured with NPCs in the presence of an OPN-neutralizing antibody resulted in OPN inhibition and reduced microglia-induced proliferation of NPCs. NPCs express integrin αvß3, which has been identified as an OPN receptor. Cilengitide, an inhibitor of integrin αvß3, also inhibited microglia-induced proliferation of NPCs. These results suggest that microglia promote the proliferation of NPCs via OPN-integrin αvß3 signaling.

B lymphocytes: Crucial contributors to brain development and neurological diseases.

The immune system is a major contributor to brain homeostasis and pathogenesis of neurological diseases. However, the role of B lymphocytes (cells) in the brain is poorly understood. In this review, we describe the functions of the different subtypes of B cells in brain development and neurological diseases. B cells are classified into several subtypes according their function and gene expression. B-1a cells, which participate in innate immunity by producing natural antibodies, are abundant in the developing brain, and mediate oligodendrocyte development. In conditions such as autoimmune encephalomyelitis, spinal cord injury, and stroke, B-2 cells exacerbate the pathology by producing pathogenic autoantibodies. On the other hand, regulatory B cells suppress inflammation by secreting interleukin-10 and play beneficial roles in pathological conditions. Here, we summarize the distribution and function of B cells during brain development and neurological diseases.

Inhibiting repulsive guidance molecule-a suppresses secondary progression in mouse models of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that is characterized by motor deficits, fatigue, pain, cognitive impairment, and sensory and visual dysfunction. Secondary progressive multiple sclerosis (SPMS) is a progressive form of MS that develops from relapsing-remitting MS. Repulsive guidance molecule-a (RGMa) has diverse functions, including axon growth inhibition and immune regulation. Here, we show inhibiting RGMa had therapeutic effects in mouse models of SPMS. We induced experimental autoimmune encephalomyelitis in nonobese diabetic mice (NOD-EAE mice) and treated them with humanized anti-RGMa monoclonal antibody. This treatment significantly suppressed secondary progression of disease and inflammation, demyelination and axonal degeneration. In addition, treatment with anti-RGMa antibody promoted the growth of corticospinal tracts and motor recovery in targeted EAE mice with inflammatory lesions in the spinal cord. Collectively, these results show that a humanized anti-RGMa antibody has therapeutic effects in mouse models of SPMS.

The role of immune cells in brain development and neurodevelopmental diseases.

During brain development, the generation of neurons and glial cells is rigorously regulated by diverse mechanisms including the immune system. Dysfunction of the developing system results in the onset of neurodevelopmental disorders and psychological disorders. Recent studies have demonstrated that the immune system is implicated in brain development. As the central nervous system is physically separated from the circulatory system by the blood-brain barrier, circulating immune cells are unable to infiltrate into the brain parenchyma. However, several studies have demonstrated that immune cells, such as B cells, T cells and macrophages, are observed in the meningeal space, perivascular space and choroid plexus and have crucial roles in brain function. Moreover, genome-wide association studies have revealed that the immune system is implicated in neurodevelopmental disorders and psychological disorders. Here, we discuss the role of each of these immune cell types in brain development and the association with neurodevelopmental disorders.

B-1a lymphocytes promote oligodendrogenesis during brain development.

During brain development, the immune system mediates neurogenesis, gliogenesis and synapse formation. However, it remains unclear whether peripheral lymphocytes contribute to brain development. Here we identified the subtypes of lymphocytes that are present in neonatal mouse brains and investigated their functions. We found that B-1a cells, a subtype of B cells, were abundant in the neonatal mouse brain and infiltrated into the brain in a CXCL13-CXCR5-dependent manner. B-1a cells promoted the proliferation of oligodendrocyte-precursor cells (OPCs) in vitro, and depletion of B-1a cells from developing brains resulted in a reduction of numbers of OPCs and mature oligodendrocytes. Furthermore, neutralizing Fcα/µR, the receptor for the Fc region of IgM secreted by B-1a cells, inhibited OPC proliferation and reduced the proportion of myelinated axons in neonatal mouse brains. Our results demonstrate that B-1a cells infiltrate into the brain and contribute to oligodendrogenesis and myelination by promoting OPC proliferation via IgM-Fcα/µR signaling.

Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica.

Neuromyelitis optica (NMO) is an autoimmune disease associated with NMO immunoglobulin G (NMO-IgG), an antibody that selectively binds to the aquaporin-4. Here, we established a localized NMO model by injecting NMO-IgG into the spinal cord, and assessed the efficacy of treating its NMO-like symptoms by blocking repulsive guidance molecule-a (RGMa), an axon growth inhibitor. The model showed pathological features consistent with NMO. Systemic administration of humanized monoclonal anti-RGMa antibody delayed the onset and attenuated the severity of clinical symptoms. Further, it preserved astrocytes and reduced inflammatory-cell infiltration and axonal damage, suggesting that targeting RGMa is effective in treating NMO.