Neuroglia (Basel, Switzerland)最新文献

{"title":"Comparison of the Transduction Capacity of AAV5 and AAV PHP.eB Serotypes in Hippocampus Astroglia","authors":"Anastasia Borodinova, Victor Ierusalimsky, Pavel Balaban","doi":"10.3390/neuroglia4040019","DOIUrl":"https://doi.org/10.3390/neuroglia4040019","url":null,"abstract":"In the present study, we compared the astrocyte-transducing potential of the relatively novel engineered AAV PHP.eB serotype and the well-examined conventional AAV5 serotype. We generated the AAV-based genetic constructs with membrane-bound fluorescent markers under the control of the astroglial promoter GfaABC1D to target astrocytes in vivo, either via local injection into the hippocampus (AAV5, AAV PHP.eB) or via systemic injection in the retro-orbital venous sinus (AAV PHP.eB). We collected new data on the transduction properties of locally injected PHP.eB and AAV5 viruses. A morphological examination and immunostainings of mouse brain slices revealed a dose-dependent shift of cellular tropism for locally injected PHP.eB from astroglial to astroglial-neuronal as the concentration increased. When the high doses of PHP.eB viruses were administered systemically, we observed strong astrocyte transduction throughout the brain, as confirmed by the morphological examination and GFAP immunostaining. AAV5 exhibited consistent astrocytic expression in all tested concentrations. The obtained results suggest that AAV5 is more suitable for astrocyte targeting in routine stereotaxic viral injection experiments. The widely used engineered PHP.eB capsid was originally designed for the transduction of both neurons and glia. Dual cellular tropism of PHP.eB viruses, observed using different doses and different delivery protocols (local vs. systemic), suggests that the usage of AAV5 is more reliable for astrocyte labeling and that intrahippocampal injection is more suitable than systemic injection for the preferential labeling of hippocampal astroglia.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":"7 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135271639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Signaling of Neuregulin-Epidermal Growth Factor Receptors and Its Impact on the Nervous System","authors":"Marzia Tagliaferro, Donatella Ponti","doi":"10.3390/neuroglia4040018","DOIUrl":"https://doi.org/10.3390/neuroglia4040018","url":null,"abstract":"The activation of members of the Epidermal Growth Factor Receptor (EGFR) family (including ErbB) triggers pathways that have significant effects on cellular processes and have profound consequences both in physiological and pathological conditions. Within the nervous system, the neuregulin (NRG)/ErbB3 signaling plays a crucial role in promoting the formation and maturation of excitatory synapses. Noteworthy is ErbB3, which is actively involved in the process of cerebellar lamination and myelination. All members of the ErbB-family, in particular ErbB3, have been observed within the nuclei of various cell types, including both full-length receptors and alternative variants. One of these variants was detected in Schwann cells and in glioblastoma primary cells where it showed a neuregulin-dependent expression. It binds to promoters’ chromatin associated with genes, like ezrin, involved in the formation of Ranvier’s node. Its nucleolar localization suggests that it may play a role in ribosome biogenesis and in cell proliferation. The regulation of ErbB3 expression is a complex and dynamic process that can be influenced by different factors, including miRNAs. This mechanism appears to play a significant role in glioblastoma and is often associated with a poor prognosis. Altogether, the targeting of ErbB3 has emerged as an active area of research in glioblastoma treatment. These findings highlight the underappreciated role of ErbB3 as a significant receptor that can potentially play a pivotal role in diverse pathologies, implying the existence of a shared and intricate mechanism that warrants further investigation.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":"257 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135918831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABAA-ρ Receptors in the CNS: Their Functional, Pharmacological, and Structural Properties in Neurons and Astroglia","authors":"Abraham Rosas-Arellano, Argel Estrada-Mondragón, Ataúlfo Martínez-Torres, Daniel Reyes-Haro","doi":"10.3390/neuroglia4040017","DOIUrl":"https://doi.org/10.3390/neuroglia4040017","url":null,"abstract":"Gamma-aminobutyric acid (GABA) is known as the main inhibitory transmitter in the central nervous system (CNS), where it hyperpolarizes mature neurons through activation of GABAA receptors, pentameric complexes assembled by combination of subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π and ρ1–3). GABAA-ρ subunits were originally described in the retina where they generate non-desensitizing Cl- currents that are insensitive to bicuculline and baclofen. However, now is known that they are widely expressed throughout the brain including glial cells. For example, whole-cell patch-clamp recordings demonstrated the functional expression of GABAA-ρ receptors in primary cultures of cerebellar astrocytes, as well as in cerebellar ependymal cells and striatal astrocytes. In these cells GABA-currents were partially blocked by TPMPA and insensitive to barbiturates. These receptors are proposed to be involved in extrasynaptic communication and dysfunction of the signaling is accompanied by reduced expression of GABAA-ρ receptors in Huntington’s disease and autism spectrum disorders (ASD). Thus, the aim of this review is to present an overview about GABAA-ρ receptors including their structure and function, as well as their importance in the excitatory/inhibitory (E/I) balance in neurodevelopment and in disease.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":"52 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135251454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of Engineered Expression of Polysialic Acid on Transplanted Schwann Cells and in Injured Rat Spinal Cord Promotes Significant Axonal Growth and Functional Recovery","authors":"Fangyou Gao, Yi Zhang, Dongsheng Wu, Juan Luo, Svetlana Gushchina, Xuenong Bo","doi":"10.3390/neuroglia4040016","DOIUrl":"https://doi.org/10.3390/neuroglia4040016","url":null,"abstract":"Providing cellular support and modifying the glial scar around the lesion are two key strategies for promoting axonal regeneration after spinal cord injury. We showed previously that over-expressing polysialic acid (PSA) on Schwann cells (SCs) by lentiviral vector (LV)-mediated expression of polysialyltransferase (PST) facilitated their integration and migration in the injured spinal cord. We also showed that PSA over-expression in the injured spinal cord modified the glial scar and promoted the growth of ascending sensory axons. In this study, we combined the PST/SC transplantation with LV/PST injection in spinal cords after dorsal column transection and found the combined treatments led to faster and more profound locomotor functional recovery compared with animals receiving combined GFP/SC transplantation with LV/GFP injection. Histological examination showed significantly more injured corticospinal axons growing close to the lesion/transplant borders and into the caudal spinal cord in the PST group than in the GFP group. We also found over -expressing PSA around the lesion site did not cause allodynia and hyperalgesia in our injury model. These results demonstrate the promising therapeutic benefit of over-expressing PSA in transplanted SCs and spinal cord in promoting axonal growth and restoring motor function.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":"71 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135966928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucose Transporter-2 Regulation of Male versus Female Hypothalamic Astrocyte MAPK Expression and Activation: Impact of Glucose.","authors":"MadhuBabu Pasula,&nbsp;Sagor C Roy,&nbsp;Khaggeswar Bheemanapally,&nbsp;Paul W Sylvester,&nbsp;Karen P Briski","doi":"10.3390/neuroglia4030011","DOIUrl":"https://doi.org/10.3390/neuroglia4030011","url":null,"abstract":"<p><p>The plasma membrane glucose transporter (GLUT)-2 is unique among GLUT family proteins in that it also functions as a glucose sensor. GLUT2 imposes sex-dimorphic control of hypothalamic astrocyte glucose storage and catabolism by unknown mechanisms. Mitogen-activated protein kinase (MAPK) signaling cascades operate within stress-sensitive signal transduction pathways. Current research employed an established primary astrocyte culture model and gene knockdown tools to investigate whether one or more of the three primary MAP kinase families are regulated by GLUT2. GLUT2 gene knockdown caused opposing adjustments in total ERK1/2 proteins in glucose-supplied male versus female astrocytes, augmenting or reducing the mean phosphorylated/total protein ratio for 44 and 42 kDa variants in these sexes. Glucose deprivation amplified this ratio for both ERK1/2 variants, albeit by a larger magnitude in male; GLUT2 siRNA exacerbated this stimulatory response in males only. Phosphorylated/total p38 MAPK protein ratios were up-regulated by GLUT2 knockdown in male, but not female astrocytes. Glucose-deprived astrocytes exhibited no change (male) or reduction (female) in this ratio after GLUT2 gene silencing. GLUT2 siRNA increased the phosphorylated/total protein ratio for 54 and 46 kDa SAPK/JNK proteins in each sex when glucose was present. However, glucose withdrawal suppressed (male) or amplified (female) these ratios, while GLUT2 knockdown attenuated these inverse responses. Results show that GLUT2 inhibits ERK1/2, p38, and SAPK/JNK MAPK activity in male, but differentially stimulates and inhibits activity of these signaling pathways in female hypothalamic astrocytes. Glucoprivation induces divergent adjustments in astrocyte p38 MAPK and SAPK/JNK activities. The findings demonstrate a stimulatory role for GLUT2 in p38 MAPK activation in glucose-starved female astrocytes, but can act as either an inhibitor or inducer of SAPK/JNK activation in glucose-deprived male versus female glial cells, respectively.</p>","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":"4 3","pages":"158-171"},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361449/pdf/nihms-1914681.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10191594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Astrocytes and Blood–Brain Barrier Disruption in Alzheimer’s Disease","authors":"J. V. R. Cruz, C. Batista, L. P. Diniz, F. Mendes","doi":"10.3390/neuroglia4030015","DOIUrl":"https://doi.org/10.3390/neuroglia4030015","url":null,"abstract":"The blood–brain barrier (BBB) is a highly intricate neurovascular structure that plays a crucial role in maintaining neural homeostasis by selectively allowing certain molecules to enter the central nervous system (CNS). However, in the context of Alzheimer’s Disease (AD), a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function, the BBB’s functionality becomes impaired. This impairment leads to the breakdown of the barrier and disrupts its ability to regulate molecular transport effectively. Consequently, cellular infiltration into the CNS occurs, along with aberrant signaling and clearance of molecules, ultimately contributing to neurological deficits. One of the key factors implicated in the failure of amyloid-beta (Aβ) transport, a hallmark of AD, is the decreased expression of low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 plays a crucial role in facilitating the transport of Aβ across the BBB. Additionally, the increased levels of the receptor for advanced glycation end products (RAGE) further contribute to the deregulation of the BBB in AD. These molecular imbalances significantly impact Aβ clearance and contribute to the development and progression of AD. In this review, we aimed to summarize the critical aspects of Aβ transporters in the BBB that become dysfunctional during the pathogenesis of AD.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49121643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overview of the Molecular Modalities and Signaling Pathways Intersecting with β-Amyloid and Tau Protein in Alzheimer’s Disease","authors":"Ahmed M. Elshazly, Melanie M. Sinanian, Diaaeldin M. Elimam, Sherin Zakaria","doi":"10.3390/neuroglia4030014","DOIUrl":"https://doi.org/10.3390/neuroglia4030014","url":null,"abstract":"Alzheimer’s disease (AD) is one of the major causes of dementia and its incidence represents approximately 60–70% of all dementia cases worldwide. Many theories have been proposed to describe the pathological events in AD, including deterioration in cognitive function, accumulation of β-amyloid, and tau protein hyperphosphorylation. Infection as well as various cellular molecules, such as apolipoprotein, micro-RNA, calcium, ghrelin receptor, and probiotics, are associated with the disruption of β-amyloid and tau protein hemostasis. This review gives an overview on the integrative cellular and signaling molecules that could play a complementary role in the dysregulation of β-amyloid and tau proteins.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45304963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the Critical Mechanisms and Functions of Neuroglia in Spinal Cord Injuries","authors":"Chih-Wei Zeng","doi":"10.3390/neuroglia4030013","DOIUrl":"https://doi.org/10.3390/neuroglia4030013","url":null,"abstract":"In the dynamic landscape of neuroscience and regenerative medicine, the pivotal role of neuroglia, or glial cells, is increasingly being recognized [...]","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48874603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Human Microglial Cell Line Expresses γ-Aminobutyric Acid (GABA) Receptors and Responds to GABA and Muscimol by Increasing Production of IL-8","authors":"Ashley Wagner, Zhimin Yan, M. Kulka","doi":"10.3390/neuroglia4030012","DOIUrl":"https://doi.org/10.3390/neuroglia4030012","url":null,"abstract":"Gamma-aminobutyric acid (GABA) is an essential neurotransmitter and an important regulator of neuroinflammation and disease. Microglia are important immune cells in the brain that express GABA receptors (GABAR) and respond to both GABA and GABAR agonists, yet the effect of GABA on microglial inflammatory responses is unclear. We hypothesized that GABA and GABAR agonists might modify the activation of a human microglial cell line (HMC3). We further hypothesized that Amanita muscaria extract (AME-1), which contained GABAR agonists (GABA and muscimol), would similarly stimulate HMC3. Ligand-gated GABAR (GABAAR) and G protein-coupled GABAR (GABABR) subunit expression was analyzed by qRT-PCR, metabolic activity was determined by nicotinamide adenine dinucleotide (NADH)-dependent oxidoreductase assay (XTT), reactive oxygen species (ROS) generation was analyzed by 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA), and interleukin-8 (IL-8) production was analyzed by an enzyme-linked immunosorbent assay (ELISA). HMC3 expressed several neuroreceptors such as subunits of the GABAA receptor (GABAAR). HMC3 constitutively produce IL-8 and ROS. Both muscimol and GABA stimulated HMC3 to produce more IL-8 but had no effect on constitutive ROS production. GABA and muscimol altered the morphology and Iba1 localization of HMC3. GABA, but not muscimol, increased HMC3 metabolic activity. Similarly, AME-1 induced HMC3 to produce more IL-8 but not ROS and altered cell morphology and Iba1 localization. GABA induction of IL-8 was blocked by bicuculline, an antagonist of GABAAR. AME-1-induced production of IL-8 was not blocked by bicuculline, suggesting that AME-1’s effect on HMC3 was independent of GABAAR. In conclusion, these data show that GABA and GABA agonists stimulate HMC3 to increase their production of IL-8. Mixtures that contain GABA and muscimol, such as AME-1, have similar effects on HMC3 that are independent of GABAAR.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44279847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focused Ultrasound-Mediated Blood–Brain Barrier Opening Best Promotes Neuroimmunomodulation through Brain Macrophage Redistribution","authors":"A. Kline-Schoder, R. Noel, H. Phatnani, V. Menon, E. Konofagou","doi":"10.3390/neuroglia4020010","DOIUrl":"https://doi.org/10.3390/neuroglia4020010","url":null,"abstract":"Neuroimmunomodulation is a promising form of drug-free treatment for neurological diseases ranging from Alzheimer’s disease to depression. The evidence supporting the efficacy of focused ultrasound (FUS) neuroimmunomodulation is encouraging; however, the method has yet to be standardized, and its mechanism remains poorly understood. Methods of FUS neuroimmunomodulation can be categorized into three paradigms based on the parameters used. In the first paradigm, focused ultrasound blood–brain barrier opening (FUS-BBBO) combines FUS with microbubbles (MB) to transiently and safely induce BBB opening. In the second paradigm, focused ultrasound neuromodulation (FUS-N) harnesses the acoustic effects of FUS alone (without MB). In the third paradigm, focused ultrasound with microbubbles without BBBO (FUS + MB) combines MB with FUS below the BBBO pressure threshold—harnessing the mechanical effects of FUS without opening the barrier. Due to the recent evidence of brain macrophage modulation in response to FUS-BBBO, we provide the first direct comparison of brain macrophage modulation between all three paradigms both in the presence and absence of Alzheimer’s disease (AD) pathology. Flow cytometry and single-cell sequencing are employed to identify FUS-BBBO as the FUS paradigm, which maximizes brain macrophage modulation, including an increase in the population of neuroprotective, disease-associated microglia and direct correlation between treatment cavitation dose and brain macrophage phagocytosis. Next, we combine spatial and single-cell transcriptomics with immunohistochemical validation to provide the first characterization of brain macrophage distribution in response to FUS-BBBO. Given their relevance within neurodegeneration and perturbation response, we emphasize the analysis of three brain macrophage populations—disease- and interferon-associated microglia and central-nervous-system-associated macrophages. We find and validate the redistribution of each population with an overall trend toward increased interaction with the brain–cerebrospinal fluid barrier (BCSFB) after FUS-BBBO, an effect that is found to be more pronounced in the presence of disease pathology. This study addresses the prior lack of FUS neuroimmunomodulation paradigm optimization and mechanism characterization, identifying that FUS-BBBO best modulates brain macrophage response via complex redistribution.","PeriodicalId":74275,"journal":{"name":"Neuroglia (Basel, Switzerland)","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47562893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}