Response Of Glial Cells Research Articles

Differentiated Embryonic Neurospheres from Familial Alzheimer's Disease Model Show Innate Immune and Glial Cell Responses.

Proteins involved in the Alzheimer's disease (AD), such as amyloid precursor protein (APP) and presenilin-1 (PS1), play critical roles in early development of the central nervous system (CNS), as well as in innate immune and glial cell responses. Familial AD is associated with the presence of APPswe and PS1dE9 mutations. However, it is still unknown whether these mutations cause deficits in CNS development of carriers. We studied genome-wide gene expression profiles of differentiated neural progenitor cells (NPCs) from wild-type and APPswe/PS1dE9 mouse embryo telencephalon. The occurrence of strong innate immune and glial cell responses in APPswe/PS1dE9 neurospheres mainly involves microglial activation, inflammatory mediators and chemokines. APPswe/PS1dE9 neurospheres augmented up to 100-fold CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF-alpha expression levels, when compared to WT neurospheres. Expression levels of the glia cell marker GFAP and microglia marker Iba-1 were up to 20-fold upregulated in APPswe/PS1dE9 neurospheres. The secretome of differentiated APPswe/PS1dE9 NPCs revealed enhanced chemoattraction of peripheral blood mononuclear cells. When evaluating the inferred protein interaction networks constructed from the array data, an improvement in astrocyte differentiation in APPswe/PS1dE9 neurosphereswas evident in view ofincreased GFAPexpression. Transgenic NPCs differentiated into neural phenotypes presented expression patterns of cytokine, glial cells, and inflammatory mediators characteristic of APPswe/PS1dE9 adult animals. Consequently, the neurogenic niche obtained from differentiation of embryonic APPswe/PS1dE9 neurospheres spontaneously presents several alterations observed in adult ADbrains. Finally, our data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for familial AD.

Regulation of TREM2 on BV2 inflammation through PI3K/AKT/mTOR pathway

ABSTRACT This work sought to determine how lipopolysaccharide (LPS)-induced pro-inflammatory factor production in BV2 microglia was influenced by myeloid cell 2 (TREM2) expressions. LPS (0.1, 1, and 10 µg/mL) induced inflammation in BV2 cells, MTT and QPCR were used to detect the occurrence of inflammation; TREM2 activation and inhibition vectors were used to activate and inhibit TREM2; Cell Proliferation was detected using CCK-8 and cell cloning experiments. LY294002 was used to inhibit the activity of PI3K/AKT signal pathway; Western blot and ELISA were used to detect cell polarization and signal pathway changes. CCK-8 and cell clone experiments found that the activation of TERM2 can promote the proliferation of BV2 cells; and the activation of TERM2 can promote the expression of IL6, IL1β, TNFα and the expression of M2 cell phenotype molecules Arg-1 and CD206. The effect of adding LY294002 signaling pathway by TERM2 activation was inhibited, indicating that TERM2 can affect the occurrence of inflammation by regulating the activity of PI3K/AKT signaling pathway. Finally, Western blotting and ELISA showed that activation of TERM2 can promote the expression of Arg-1 and CD206 in BV2 cells, and promote the transformation of BV2 cells to M2 polarization. TERM2 can affect the inflammatory response in microglia through the PI3K/AKT signaling pathway, suggesting that TERM2 may be a target for the treatment of inflammatory response in glial cells. This study provides a treatment plan for alleviating the impact of inflammation on central nervous system.

NOD-like receptor NLRC5 promotes neuroinflammation and inhibits neuronal survival in Parkinson’s disease models

Parkinson’s disease (PD) is mainly characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neuroinflammation mediated by overactivated microglia and astrocytes. NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) has been reported to participate in various immune disorders, but its role in neurodegenerative diseases remains unclear. In the current study, we found that the expression of NLRC5 was increased in the nigrostriatal axis of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD, as well as in primary astrocytes, microglia and neurons exposed to different neurotoxic stimuli. In an acute MPTP-induced PD model, NLRC5 deficiency significantly reduced dopaminergic system degeneration and ameliorated motor deficits and striatal inflammation. Furthermore, we found that NLRC5 deficiency decreased the expression of the proinflammatory genes IL-1β, IL-6, TNF-α and COX2 in primary microglia and primary astrocytes treated with neuroinflammatory stimuli and reduced the inflammatory response in mixed glial cells in response to LPS treatment. Moreover, NLRC5 deficiency suppressed activation of the NF-κB and MAPK signaling pathways and enhanced the activation of AKT–GSK-3β and AMPK signaling in mixed glial cells. Furthermore, NLRC5 deficiency increased the survival of primary neurons treated with MPP+ or conditioned medium from LPS-stimulated mixed glial cells and promoted activation of the NF-κB and AKT signaling pathways. Moreover, the mRNA expression of NLRC5 was decreased in the blood of PD patients compared to healthy subjects. Therefore, we suggest that NLRC5 promotes neuroinflammation and dopaminergic degeneration in PD and may serve as a marker of glial activation.

Innate and adaptive glial cell responses in Alzheimer’s disease

Alzheimer’s disease (AD), which affects around twenty-seven million people globally, is an aging-related neurodegenerative condition characterized by the extracellular deposition of misfolded amyloid-β (Aβ) peptides and the intracellular production of neurofibrillary tangles (NFTs) AD results from the death of certain groups of neurons in the brain while appearing to have no impact on neighboring neurons. It is progressive and incurable. Therefore, the pathophysiology of afflicted populations and the development of intervention measures to stop neuronal cell death have been the main areas of attention for delineating therapeutic options. Proinflammatory cytokines are responsible for the stimulation of inflammatory responses and are mostly generated by activated macrophages in the brain. This review discusses how glial cells and innate and adaptive immune responses have a critical role in AD. It also provides information about microglial activation through the cluster of differentiation 40 (CD40) ligation and CD40L. CD40L ligation of microglial CD40 results in a large increase in tumor necrosis factor-α (TNF-α) production. Cultured cortical neuronal injury is caused when microglia are activated by CD40 ligation in the presence of interferon-γ (IFN-γ). This injury is significantly reduced by blocking the CD40 pathway or neutralising TNF-α. The management of AD would require integrating all available information about the innate and adaptive immune response affecting AD-related neuronal death.

Reduced non-CpG methylation is a potential epigenetic target after spinal cord injury.

DNA methylation is a critical epigenetic regulator in the occurrence and development of diseases and is closely related to various functional responses in relation to spinal cord injury. To investigate the role of DNA methylation in spinal cord injury, we constructed a library with reduced-representation bisulfite sequencing data obtained at various time points (day 0-42) after spinal cord injury in mice. Global DNA methylation levels, specifically non-CpG (CHG and CHH) methylation levels, decreased modestly following spinal cord injury. Stages post-spinal cord injury were classified as early (day 0-3), intermediate (day 7-14), and late (day 28-42) based on similarity and hierarchical clustering of global DNA methylation patterns. The non-CpG methylation level, which included CHG and CHH methylation levels, was markedly reduced despite accounting for a minor proportion of total methylation abundance. At multiple genomic sites, including the 5' untranslated regions, promoter, exon, intron, and 3' untranslated regions, the non-CpG methylation level was markedly decreased following spinal cord injury, whereas the CpG methylation level remained unchanged at these locations. Approximately one-half of the differentially methylated regions were located in intergenic areas; the other differentially methylated regions in both CpG and non-CpG regions were clustered in intron regions, where the DNA methylation level was highest. The function of genes associated with differentially methylated regions in promoter regions was also investigated. From Gene Ontology analysis results, DNA methylation was implicated in a number of essential functional responses to spinal cord injury, including neuronal synaptic connection creation and axon regeneration. Notably, neither CpG methylation nor non-CpG methylation was implicated in the functional response of glial or inflammatory cells. In summary, our work elucidated the dynamic pattern of DNA methylation in the spinal cord following injury and identified reduced non-CpG methylation as an epigenetic target after spinal cord injury in mice.

Single-cell multiome sequencing clarifies enteric glial diversity and identifies an intraganglionic population poised for neurogenesis

The enteric nervous system (ENS) consists of glial cells (EGCs) and neurons derived from neural crest precursors. EGCs retain capacity for large-scale neurogenesis in culture, and invivo lineage tracing has identified neurons derived from glial cells in response to inflammation. We thus hypothesize that EGCs possess a chromatin structure poised for neurogenesis. We use single-cell multiome sequencing to simultaneously assess transcription and chromatin accessibility in EGCs undergoing spontaneous neurogenesis in culture, as well as small intestine myenteric plexus EGCs. Cultured EGCs maintain open chromatin at genomic loci accessible in neurons, and neurogenesis from EGCs involves dynamic chromatin rearrangements with a net decrease in accessible chromatin. A subset of invivo EGCs, highly enriched within the myenteric ganglia and that persist into adulthood, have a gene expression program and chromatin state consistent with neurogenic potential. These results clarify the mechanisms underlying EGC potential for neuronal fate transition.

Impact of Plant-Derived Compounds on Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by progressive motor neuron degeneration. Conventional therapies for ALS are based on treatment of symptoms, and the disease remains incurable. Molecular mechanisms are unclear, but studies have been pointing to involvement of glia, neuroinflammation, oxidative stress, and glutamate excitotoxicity as a key factor. Nowadays, we have few treatments for this disease that only delays death, but also does not stop the neurodegenerative process. These treatments are based on glutamate blockage (riluzole), tyrosine kinase inhibition (masitinib), and antioxidant activity (edaravone). In the past few years, plant-derived compounds have been studied for neurodegenerative disorder therapies based on neuroprotection and glial cell response. In this review, we describe mechanisms of action of natural compounds associated with neuroprotective effects, and the possibilities for new therapeutic strategies in ALS.

The link between neuroinflammation and the neurovascular unit in synucleinopathies.

The neurovascular unit (NVU) is composed of vascular cells, glial cells, and neurons. As a fundamental functional module in the central nervous system, the NVU maintains homeostasis in the microenvironment and the integrity of the blood-brain barrier. Disruption of the NVU and interactions among its components are involved in the pathophysiology of synucleinopathies, which are characterized by the pathological accumulation of α-synuclein. Neuroinflammation contributes to the pathophysiology of synucleinopathies, including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. This review aims to summarize the neuroinflammatory response of glial cells and vascular cells in the NVU. We also review neuroinflammation in the context of the cross-talk between glial cells and vascular cells, between glial cells and pericytes, and between microglia and astroglia. Last, we discuss how α-synuclein affects neuroinflammation and how neuroinflammation influences the aggregation and spread of α-synuclein and analyze different properties of α-synuclein in synucleinopathies.

Phospholipase B Is Critical for Cryptococcus neoformans Survival in the Central Nervous System.

Cryptococcus neoformans (Cn) is an opportunistic, encapsulated, yeast-like fungus that causes severe meningoencephalitis, especially in countries with high HIV prevalence. In addition to its well-known polysaccharide capsule, Cn has other virulence factors such as phospholipases, a heterogeneous group of enzymes that hydrolyze ester linkages in glycerophospholipids. Phospholipase B (PLB1) has been demonstrated to play a key role in Cn pathogenicity. In this study, we used a PLB1 mutant (plb1) and its reconstituted strain (Rec1) to assess the importance of this enzyme on Cn brain infection in vivo and in vitro. Mice infected with the plb1 strain survive significantly longer, have lower peripheral and central nervous system (CNS) fungal loads, and have fewer and smaller cryptococcomas or biofilm-like brain lesions compared to H99- and Rec1-infected animals. PLB1 causes extensive brain tissue damage and changes microglia morphology during cryptococcal disease, observations which can have important implications in patients with altered mental status or dementia as these manifestations are related to poorer survival outcomes. plb1 cryptococci are significantly more phagocytosed and killed by NR-9460 microglia-like cells. plb1 cells have altered capsular polysaccharide biophysical properties which impair their ability to stimulate glial cell responses or morphological changes. Here, we provide significant evidence demonstrating that Cn PLB1 is an important virulence factor for fungal colonization of and survival in the CNS as well as in the progression of cryptococcal meningoencephalitis. These findings may potentially help fill in a gap of knowledge in our understanding of cerebral cryptococcosis and provide novel research avenues in Cn pathogenesis. IMPORTANCE Cryptococcal meningoencephalitis (CME) is a serious disease caused by infection by the neurotropic fungal pathogen Cryptococcus neoformans. Due to the increasing number of cases in HIV-infected individuals, as well as the limited therapies available, investigation into potential targets for new therapeutics has become critical. Phospholipase B is an enzyme synthesized by Cn that confers virulence to the fungus through capsular enlargement, immunomodulation, and intracellular replication. In this study, we examined the properties of PLB1 by comparing infection of a Cn PLB1 mutant strain with both the wild-type and a PLB1-reconstituted strain. We show that PLB1 augments the survival and proliferation of the fungus in the CNS and strengthens virulence by modulating the immune response and enhancing specific biophysical properties of the fungus. PLB1 expression causes brain tissue damage and impacts glial cell functions, which may be responsible for the dementia observed in patients which may persist even after resolving from CME. The implications of PLB1 inhibition reveal its involvement in Cn infection and suggest that it may be a possible molecular target in the development of antifungal therapies. The results of this study support additional investigation into the mechanism of PLB1 to further understand the intricacies of cerebral Cn infection.

High-fat diet feeding triggers a regenerative response in the adult zebrafish brain.

Non-alcoholic fatty liver disease (NAFLD) includes a range of liver conditions ranging from excess fat accumulation to liver failure. NAFLD is strongly associated with high-fat diet (HFD) consumption that constitutes a metabolic risk factor. While HFD has been elucidated concerning its several systemic effects, there is little information about its influence on the brain at the molecular level. Here, by using a high-fat diet (HFD)-feeding of adult zebrafish, we first reveal that excess fat uptake results in weight gain and fatty liver. Prolonged exposure to HFD induces a significant increase in the expression of pro-inflammation, apoptosis, and proliferation markers in the liver and brain tissues. Immunofluorescence analyses of the brain tissues disclose stimulation of apoptosis and widespread activation of glial cell response. Moreover, glial activation is accompanied by an initial decrease in the number of neurons and their subsequent replacement in the olfactory bulb and the telencephalon. Long-term consumption of HFD causes activation of Wnt/β-catenin signaling in the brain tissues. Finally, fish fed an HFD induces anxiety, and aggressiveness and increases locomotor activity. Thus, HFD feeding leads to a non-traumatic brain injury and stimulates a regenerative response. The activation mechanisms of a regeneration response in the brain can be exploited to fight obesity and recover from non-traumatic injuries.

Exosomes from Inflamed Macrophages Promote the Progression of Parkinson's Disease by Inducing Neuroinflammation.

Inflammation is a common feature both for Parkinson's disease (PD) and obesity-associated metabolic syndromes. Inflammation mediated by inflamed macrophages in white adipose tissue plays a pivotal role for the pathogenesis of metabolic syndromes. Exosomes are important carriers connecting peripheral tissues and the central nervous system (CNS). Therefore, we speculate that exosomes derived from inflamed macrophages may be involved in the pathological progression of PD. Here, we prepared exosomes from lipopolysaccharide (LPS) or interferon gamma (IFNγ) treated macrophages (inflamed macrophages) and examined their potential roles in PD. Our data showed that exosomes from inflamed macrophages stimulate proinflammatory cytokine expression in primary microglia and astrocytes. In vivo, inflamed macrophage exosomes induce behavioral defects in mice as evidenced by shortened duration in the rotarod test and prolonged latency in the pole test. The treatment of exosomes also reduces tyrosine hydroxylase (TH) positive cells in the substantia nigra pars compacta (SNpc) and striatum. All these PD-like phenotypes are likely due to the activation of microglia and astrocytes induced by exosomes from inflamed macrophages. Exosome sequencing, together with bioinformatics analysis and functional studies, revealed that exosomal miRNAs such as miR-155-5p are likely a key factor for inducing an inflammatory response in glial cells. These results indicate that exosomes derived from inflamed macrophages are likely a causative factor for developing PD. In this regard, inflamed macrophage exosomes might be a linker transducing the peripheral tissue inflammation into the CNS.

The multitaskers of the brain: Glial responses to viral infections and associated post-infectious neurologic sequelae.

Many viral infections cause acute and chronic neurologic diseases which can lead to degeneration of cortical functions. While neurotropic viruses that gain access to the central nervous system (CNS) may induce brain injury directly via infection of neurons or their supporting cells, they also alter brain function via indirect neuroimmune mechanisms that may disrupt the blood-brain barrier (BBB), eliminate synapses, and generate neurotoxic astrocytes and microglia that prevent recovery of neuronal circuits. Non-neuroinvasive, neurovirulent viruses may also trigger aberrant responses in glial cells, including those that interfere with motor and sensory behaviors, encoding of memories and executive function. Increasing evidence from human and animal studies indicate that neuroprotective antiviral responses that amplify levels of innate immune molecules dysregulate normal neuroimmune processes, even in the absence of neuroinvasion, which may persist after virus is cleared. In this review, we discuss how select emerging and re-emerging RNA viruses induce neuroimmunologic responses that lead to dysfunction of higher order processes including visuospatial recognition, learning and memory, and motor control. Identifying therapeutic targets that return the neuroimmune system to homeostasis is critical for preventing virus-induced neurodegenerative disorders.

Dietary ingredient change induces a transient MyD88-dependent mucosal enteric glial cell response and promotes obesity

ABSTRACT Objective Consumption of a modern Western-type high-fat low-fiber diet increases the risk of obesity. However, how a host responds to such a diet, especially during the early period of dietary transition from a previous low-fat and fiber-rich diet, remains poorly explored. Methods Wild-type C57BL/6 mice were fed a normal chow diet or a high-fat diet. Enteric glial cell (EGC) activation was detected through quantitative real-time PCR (qRT-PCR), immunoblotting and immunohistology analysis. Fluorocitrate or genetic deletion of glial fibrillary acidic protein (GFAP)-positive glial-intrinsic myeloid differentiation factor 88 (Myd88) was used to inhibit EGC activation, and the effect of a high-fat diet on obesity was further investigated. The role of MYD88-dependent sensing of commensal products in adipocyte was observed to analyze the effect of obesity. Results A dietary shift from a normal chow diet to a high-fat diet in mice induced a transient early-phase emergence of a GFAP-positive EGC network in the lamina propria of the ileum, accompanied with an increase in glial-derived neurotrophic factor production. Inhibition of glial cell activity blocked this response. GFAP-positive glial Myd88 knockout mice gained less body weight after high-fat diet (HFD) feeding than littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no effect on weight gain but instead exacerbated glucose intolerance. Furthermore, short-term fluorocitrate intervention during HFD feeding attenuated body weight gain. Conclusions Our findings indicate that EGCs are early responders to intestinal ecosystem changes and the GFAP-positive glial Myd88 signaling participates in regulating obesity.

Factors Associated with Elevated Tumor Necrosis Factor-α in Aqueous Humor of Patients with Open-Angle Glaucoma.

Tumor necrosis factor-alpha (TNF-α) is an important modulator of neuroinflammation, secreted from activated glial cells in response to intraocular stress. The purpose of this study was to investigate the clinical factors associated with elevated TNF-α and its level in aqueous humor of patients with open-angle glaucoma (OAG). Aqueous humor was collected from 73 OAG eyes, and TNF-α level was analyzed using the singleplex bead immunoassay method. Patients were divided into TNF-α-positive and TNF-α-negative groups according to the TNF-α level of 10 pg/mL, and baseline clinical characteristics were compared. The TNF-α-positive group showed higher baseline IOP, greater IOP fluctuation, and higher systolic blood pressure than the TNF-α-negative group (p = 0.007, p < 0.001, and p = 0.009, respectively). In the multivariate logistic regression analysis, IOP fluctuation (p = 0.037) and systolic blood pressure (p = 0.016) were all independently associated with positive TNF-α level. In normal-tension glaucoma (NTG) patients, presence of central scotoma (p = 0.029) was significantly associated with positive TNF-α level. In conclusion, positive TNF-α level in OAG patients was associated with greater IOP fluctuation and higher systolic blood pressure. In NTG patients, positive TNF-α level was associated with the presence of central scotoma. IOP factors and vascular factors, including blood pressure and presence of central scotoma, may indicate glaucoma pathogenesis related to TNF-α elevation in OAG patients.

Disruption of Calcium Homeostasis and Following Changes in Calcium Signaling in Neurons and Glial Cells in Response to Photodynamic Treatment

Disruption of Calcium Homeostasis and Following Changes in Calcium Signaling in Neurons and Glial Cells in Response to Photodynamic Treatment

Adeno-associated virus (AAV) 9-mediated gene delivery of Nurr1 and Foxa2 ameliorates symptoms and pathologies of Alzheimer disease model mice by suppressing neuro-inflammation and glial pathology.

There is a compelling need to develop disease-modifying therapies for Alzheimer's disease (AD), the most common neuro-degenerative disorder. Together with recent progress in vector development for efficiently targeting the central nervous system, gene therapy has been suggested as a potential therapeutic modality to overcome the limited delivery of conventional types of drugs to and within the damaged brain. In addition, given increasing evidence of the strong link between glia and AD pathophysiology, therapeutic targets have been moving toward those addressing glial cell pathology. Nurr1 and Foxa2 are transcription/epigenetic regulators that have been reported to cooperatively regulate inflammatory and neurotrophic response in glial cells. In this study, we tested the therapeutic potential of Nurr1 and Foxa2 gene delivery to treat AD symptoms and pathologies. A series of functional, histologic, and transcriptome analyses revealed that the combined expression of Nurr1 and Foxa2 substantially ameliorated AD-associated amyloid β and Tau proteinopathy, cell senescence, synaptic loss, and neuro-inflammation in multiple in vitro and in vivo AD models. Intra-cranial delivery of Nurr1 and Foxa2 genes using adeno-associated virus (AAV) serotype 9 improved the memory and cognitive function of AD model mice. The therapeutic benefits of gene delivery were attained mainly by correcting pathologic glial function. These findings collectively indicate that AAV9-mediated Nurr1 and Foxa2 gene transfer could be an effective disease-modifying therapy for AD.

Astrocyte Activation, but not Microglia, Is Associated with the Experimental Mouse Model of Schizophrenia Induced by Chronic Ketamine.

Ketamine is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. Many experimental studies have shown that ketamine can induce cognitive impairments and schizophrenia-like symptoms. While much data have demonstrated that glial cells are associated with the pathophysiology of psychiatric disorders, including schizophrenia, the response of glial cells to ketamine and its significance to schizophrenia are not clear. The present study was intended to explore whether chronic ketamine treatment would induce behavioral and glial changes in mice. First, ketamine was used to stimulate behavioral abnormalities similar to schizophrenia evaluated by the open field test, elevated plus-maze test, Y maze test, novel object recognition test, and tail suspension test. Secondly, histopathology and Nissl staining were performed. Meanwhile, immunofluorescence was used to evaluate the expression levels of IBA-1 (a microglial marker) and GFAP (an astrocyte marker) in the mouse hippocampus for any change. Then, ELISA was used to analyze proinflammatory cytokine levels for any change. Our results showed that ketamine (25mg/kg, i.p., qid, 12days) induced anxiety, recognition deficits, and neuronal injury in the hippocampus. Moreover, chronic ketamine treatment enhanced GFAP expression in CA1 and DG regions of the hippocampus but did not influence the expression of IBA-1. Ketamine also increased the levels of IL-1β, IL-6, and TNF-α in the mouse hippocampus. Our study created a new procedure for ketamine administration, which successfully induce negative symptoms and cognitive-behavioral defects in schizophrenia by chronic ketamine. This study furtherrevealed that an increase in astrocytosis, but not microglia, is associated with the mouse model of schizophrenia caused by ketamine. In summary, hippocampal astrocytes may be involved in the pathophysiology of ketamine-induced schizophrenia-like phenotypes through reactive transformation and regulation of neuroinflammation.

Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated α-synuclein mouse model of Parkinson's disease

The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in the hm2α-SYN-39 mouse model of PD that carries the human, A30P/A53T double-mutated α-synuclein gene. At 2–3 months of age, no significant differences were observed comparing dopaminergic neuron numbers of the substantia nigra (SN) pars compacta of hm2α-SYN-39 mice with wildtype controls. At an age of 16–17 months, however, hm2α-SYN-39 mice revealed a significant loss of dopaminergic SN neurons, of dopaminergic terminals in the striatum as well as a reduction of striatal dopamine levels compared to young, 2–3 months transgenic mice and compared to 16–17 months old wildtype littermates. A significant age-related correlation of infiltrating CD4+ and CD8+ T cell numbers with dopaminergic terminal loss of the striatum was found in hm2α-SYN-39 mice, but not in wildtype controls. In the striatum of 16–17 months old wildtype mice a slightly elevated CD8+ T cell count and CD11b+ microglia cell count was observed compared to younger aged mice. Additional analyses of neuroinflammation in the nigrostriatal tract of wildtype mice did not yield any significant age-dependent changes of CD4+, CD8+ T cell and B220+ B cell numbers, respectively. In contrast, a significant age-dependent increase of CD8+ T cells, GFAP+ astrocytes as well as a pronounced increase of CD11b+ microglia numbers were observed in the SN of hm2α-SYN-39 mice pointing towards a neuroinflammatory processes in this genetic mouse model for PD. The findings in the hm2α-SYN-39 mouse model strengthen the evidence that T cell and glial cell responses are involved in the age-related neurodegeneration in PD. The slow and age-dependent progression of neurodegeneration and neuroinflammation in the hm2α-SYN-39 PD rodent model underlines its translational value and makes it suitable for studying anti-inflammatory therapies.

Glycometabolism Reprogramming of Glial Cells in Central Nervous System: Novel Target for Neuropathic Pain.

Neuropathic pain is characterized by hyperalgesia and allodynia. Inflammatory response is conducive to tissue recovery upon nerve injury, but persistent and exaggerated inflammation is detrimental and participates in neuropathic pain. Synaptic transmission in the nociceptive pathway, and particularly the balance between facilitation and inhibition, could be affected by inflammation, which in turn is regulated by glial cells. Importantly, glycometabolism exerts a vital role in the inflammatory process. Glycometabolism reprogramming of inflammatory cells in neuropathic pain is characterized by impaired oxidative phosphorylation in mitochondria and enhanced glycolysis. These changes induce phenotypic transition of inflammatory cells to promote neural inflammation and oxidative stress in peripheral and central nervous system. Accumulation of lactate in synaptic microenvironment also contributes to synaptic remodeling and central sensitization. Previous studies mainly focused on the glycometabolism reprogramming in peripheral inflammatory cells such as macrophage or lymphocyte, little attention was paid to the regulation effects of glycometabolism reprogramming on the inflammatory responses in glial cells. This review summarizes the evidences for glycometabolism reprogramming in peripheral inflammatory cells, and presents a small quantity of present studies on glycometabolism in glial cells, expecting to promote the exploration in glycometabolism in glial cells of neuropathic pain.

Intravitreal and subretinal syngeneic bone marrow mononuclear stem cell transplantation improves photoreceptor survival but does not ameliorate retinal function in two rat models of retinal degeneration.

To study and compare effects of syngeneic bone marrow mononuclear stem cells (BM-MNCs) transplants on inherited retinal degeneration in two animal models with different etiologies: the RCS and the P23H-1 rats. To compare the safety and efficacy of two methods of intraocular delivery: subretinal and/or intravitreal. A suspension of BM-MNCs was injected subretinally or intravitreally in the left eyes of P23H-1 and RCS rats at post-natal day (P) 21. At different survival intervals after the injection: 7, 15, 30 or 60 days, the retinas were cross-sectioned, and photoreceptor survival and glial cell responses were investigated using immunodetection of cones (anti-cone arrestin), synaptic connections (anti-bassoon), microglia (anti-Iba-1), astrocytes and Müller cells (anti-GFAP). Electroretinographic function was also assessed longitudinally. Intravitreal injections (IVIs) or subretinal injections (SRIs) of BM-MNCs did not produce adverse effects. The transplanted cells survived for up to 15 days but did not penetrate the retina. Both IVIs and SRIs increased photoreceptor survival, decreased synaptic degeneration and glial fibrillary acidic protein (GFAP) expression in Müller cells but did not modify microglial cell activation and migration or the electroretinographic responses. Intravitreal and subretinal syngeneic BM-MNCs transplantation decreases photoreceptor degeneration and shows anti-gliotic effects on Müller cells but does not ameliorate retinal function. Moreover, syngeneic BM-MNCs transplants are more effective than the xenotransplants of these cells. BM-MNC transplantation has potential therapeutic effects that merit further investigation.