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Lipopolysaccharides and leukotriene B4 induce independently regulated electrophysiological and immunological responses in cultured astrocytes.

Astrocytes play an important role in immunological processes within the central nervous system. They are able to produce cytokines like interleukin 6 (IL-6) and depolarize substantially after stimulation by lipopolysaccharides (LPS) or leukotriene B4 (LTB4). Therefore, we investigated the coupling between these immunological and electrophysiological processes. Amiloride (250 microM), a blocker of various Na+ transport systems, inhibited LPS (5 micrograms/ml)-induced depolarization, whereas the LPS-induced release of IL-6 was unaffected, indicating different intracellular regulatory mechanisms.…

Developmental expression of the proenkephalin and prosomatostatin genes in cultured cortical and cerebellar astrocytes.

Astrocytes were prepared from rats of 4 ages, embryonic day 20, postnatal days 3 and 8, and adult, in order to study the developmental time course of expression of enkephalin and somatostatin (SS). Glial fibrillary acidic protein (GFAP) content was constant in both cortical and cerebellar astrocytes prepared from all ages. SS mRNA and peptide decreased over this developmental time course in cerebellar astrocytes; the time course of changes in SS mRNA paralleled that for rat cerebellum. Proenkephalin (PE) mRNA increased about 3-fold in cerebellar astrocytes from embryonic day 20 to adult but re…

Effects of mercury and lead on rubidium uptake and efflux in cultured rat astrocytes.

Astrocytes readily sequester lead and mercury (8, 10, 19, 22). Accordingly, studies were undertaken to assess the effects of lead and mercury on homeostatic functions in neonatal rat brain primary astrocyte cultures. Both inorganic and organic mercury, but not lead, significantly inhibited the initial rate (5 min) of uptake of 86RbCl, used as a tracer for K+, at concentrations of 10-100 microM. Mercury and to a lesser extent lead also stimulated the efflux of intracellular 86Rb+ at 10-500 microM. These observations suggest that the astrocyte plasma membrane may be an important target for lead …

Taurine-deficient cultured cerebellar astrocytes and granule neurons obtained by treatment with guanidinoethane sulfonate.

Mouse cerebellar granule neurons and astrocytes grown in the presence of 2 mM guanidinoethane sulfonate (GES) exhibited a progressive and rapid decrease in taurine concentration. A reduction of 20% was observed as early as 1 hr after exposure to GES and the loss of cell taurine continued until the taurine pool was reduced by about 90%. This remaining taurine persisted without further decrease even after 3 weeks of exposure to GES. Taurine reduction caused by GES was similar in both types of cells. The effect of GES was dose-dependent, with significant decreases in taurine levels already detect…

Human fetal astrocytes in culture support the growth of the neurotropic human polyomavirus, JCV.

JC virus (JCV) has frequently been described as a tissue specific agent in the human population targeting the myelin producing oligodendrocyte whose destruction results in the demyelinating disease, progressive multifocal leukoencephalopathy (PML). JC virus growth in cell culture systems has generally reflected that observation because its multiplication is most efficient in cultures derived from human fetal brain. These cultures, however, are composed of a mixed population of cells phenotypically categorized as either astrocytes or precursors to oligodendrocytes. We have been able to separate…

Astrocyte targeted SMN1 gene therapy and forskolin application improves astrocyte filopodia actin defects and motor neuron synaptic dysfunction in human SMA disease pathology.

BACKGROUND: Peri-synaptic astrocyte processes (PAPs) play a fundamental role in synapse formation and function. Central afferent synapse los … al and super resolution microscopy, synaptogliosome isolation, and electrophysiology. RESULTS: SMA astrocytes demonstrated intrinsic filopodia actin defects featuring low abundance of actin-associated cell surface N-glycoproteins, and decreased filopodia density and CDC42-GTP levels after actin remodeling stimulation. This phenotype is likely driven by the …

Ellagic acid regulates astrocytic responses under inflammatory conditions in primary astrocyte cultures: effects on oxidative stress, inflammatory cytokines, and glycogen synthase kinase-3β.

BACKGROUND: Neuroinflammation involves the activation of glial cells, particularly astrocytes, and microglia, in response to pathological stimuli. Astrocyte activation is characterized by increased pro-inflammatory cytokines and oxidative stress. Given their role in neuroinflammation, targeting astrocytic mechanisms presents potential therapeutic opportunities. Ellagic acid (EA), a phenolic compound, exhibits antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated the effect of EA on astrocytes from neonatal rats exposed to lipopolysaccharide (LPS), a potent proinf…

Bone marrow stromal cells induce BMP2/4 production in oxygen-glucose-deprived astrocytes, which promotes an astrocytic phenotype in adult subventricular progenitor cells.

Bone morphogenetic proteins (BMPs) affect cell proliferation and differentiation. Astrocytes in ischemic brain are highly responsive to bone marrow stromal cell (BMSC) treatment. We investigated the effects of BMSCs on astrocytes cultured under oxygen- and glucose-deprived conditions, which in part simulate in vivo stroke conditions, to test the hypothesis that BMSCs alter astrocytic expression of BMPs which may contribute to neurological functional recovery of stroke. Quantitative real-time RT-PCR showed that the expression of BMP2/4 mRNAs decreased within ischemic astrocytes, In contrast, BM…

TLR3 activation in astrocytes attenuates the nigrostriatal pathway degeneration in rodent models of Parkinson's disease.

Toll-like receptor 3 (TLR3) is classically known for mediating inflammatory pathways in Parkinson's disease (PD). However, the role of TLR3 in nigrostriatal degeneration in PD remains unclear. Here, we observed that TLR3 is predominantly expressed on astrocytes in the substantia nigra in both human PD brain and in rat PD models induced by intra-MFB injection of 1-methyl-4-phenylpyridinium (MPP+). Interestingly, Poly I: C, an activator of TLR3, significantly induced TLR3 expression on astrocytes. Treatment with Poly I: C markedly attenuated nigral dopamine neuron death in the PD rat models. The…

Activated microglia contribute to paraquat neurotoxicity through neuroinflammation and regulation of phenotypic polarization of astrocytes.

Paraquat (PQ), a widely used bipyridyl herbicide, exerts neurotoxic effects on dopaminergic neurons and can lead to Parkinson's disease (PD) … hat PQ exposure induced neuroinflammation, dopaminergic neuron degeneration, and a pro-inflammatory astrocytes phenotype, all of which were reversed by microglial depletion. In vitro experiments using primary astrocytes cultured in conditioned medium from PQ-activated microglia demonstrated that activated microglia promoted a pro-inflammatory astrocyte pheno …

Astrocytes Coordinate Neurovascular Coupling During Prolonged Sensory Demand via AQP4/TRPA1/BEST1/D-Serine Signaling.

Astrocytes are recognized as key components of neurovascular coupling (NVC), yet whether and how astrocytic engagement in NVC depends on sensory stimulus duration remains unclear. Here, we investigated a duration-dependent astrocytic mechanism underlying cerebral blood volume (CBV) modulation by comparing neurovascular responses to brief (5 s) and prolonged (20 s) sensory stimulation, using in vivo intrinsic optical signal (IOS) imaging and two-photon microscopy combined with electrophysiology and vascular cannulation. We show that prolonged stimulation selectively recruits an integrated astro…

Metabolic Status and Morphological Changes of Astrocytes under Reductive Stress in vitro: Neural Network Analysis.

Reductive stress caused by excessive accumulation of reducing equivalents (NADH, NADPH, glutathione), is increasingly recognized as a pathogenetic factor at the early stages of neurodegenerative diseases. However, its impact on the morphofunctional properties of astrocytes remains poorly understood. We performed the first comprehensive quantitative assessment of biochemical and morphological changes in cultured primary rat astrocytes under chronic reductive stress modeled using dithiothreitol (DTT, 500 μM, 24 h). To enable morphometric analysis of live, unstained cells, we developed and traine…

Single-cell analysis of sterol-induced Ca2＋ signaling in human astrocytes by dynamic mode decomposition.

Ca2＋ signaling in astrocytes is a central mechanism of intercellular communication in the brain and plays a key role in regulating neuronal excitability, synaptic plasticity, and energy metabolism. Disruption of astrocytic Ca2＋ dynamics is a characteristic of neurodegenerative diseases, as are deviations in cholesterol trafficking and metabolism, which are essential for maintaining membrane structure and function. Although recent studies have begun to explore links between Ca2＋ signaling and sterol homeostasis in astrocytes, unbiased analytical workflows and mechanistic insight into how choles…

Spatio-Temporal Expression Patterns of Connexins 43 and 30 in Hippocampal Astrocytes During Postnatal Development.

Astrocytes are extensively interconnected via gap junction channels formed primarily by connexin 43 (Cx43) and connexin 30 (Cx30), two proteins that play central roles in intercellular signaling and homeostatic regulation in the brain. Although the functional properties of these connexins have been widely investigated, their spatial organization within astrocytes and its evolution during postnatal development remain poorly characterized. Here, we combined confocal and stimulated emission depletion (STED) super-resolution microscopy to examine the expression, distribution and colocalization of …

Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.

Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with …

Вирус Zika усугубляет энцефаломиэлит, вызывая производство хемокина Т в астроцитах.

Недавние вспышки вируса ZIKA (ZIKV) в Бразилии и Пуэрто-Рико были связаны с ростом заболеваемости микроцефалией плода и синдромом Гильен-Барре. Кроме того, хотя причинно-следственная связь до сих пор не доказана, ZIKV был обнаружен в мозгах пациентов с множественным склерозом (MS), что вызвало интерес к возможной связи. Цель настоящего исследования заключалась в разъяснении роли ZIKV в патогенезе MS. Зараженные ZIKV мыши с экспериментальным аутоиммунным энцефаломиелитом (EAE) продемонстрировали симптомы отягчающего действия EAE при значительном обезвоживании центральной нервной системы (CNS).

Совпадение в аннотации оригинала
Recent outbreaks of the ZIKA virus (ZIKV) in Brazil and Puerto Rico have been linked to an increase in the incidence of fetal microcephaly a … into the CNS by enhancing the expression of chemokines for C-C motif chemokine receptor 2 (CCR2) in astrocytes, which was dependent on tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling. Propagermanium, a CCR2 inhibitor, prevented ZIKV-induced exacerbation of EAE in mice. These findings highlight the critical role of TRAF6 signaling in the …

Photoactivated adenylyl cyclase in cortical astrocytes promotes synaptic potentiation and reveals alterations in Huntington's disease.

Coordinated neuron-astrocyte interactions are crucial for synaptic plasticity and brain function. Cyclic adenosine monophosphate (cAMP) pathways have a key role in modulating plasticity and are disrupted in neurodegenerative diseases. Yet, the role of astrocytic cAMP remains unclear. We addressed this by expressing the photoactivatable adenylyl cyclase DdPAC in cortical astrocytes, enabling cAMP synthesis under red light stimulation. Using electrophysiological and comprehensive proteomic analyses, we determined its effects in wild-type mice. The modulation of astrocytic cAMP triggered long-ter…

CRISPRi screening in cultured human astrocytes uncovers distal enhancers controlling genes dysregulated in Alzheimer's disease.

Genetic variants associated with complex traits often lie in distal enhancers. While candidate enhancers have been mapped genome wide, their functional state and gene targets in specific cell types remain unclear. Here we present AstroREG, a resource of enhancer-gene interactions in human primary astrocytes, generated by combining CRISPR inhibition (CRISPRi), single-cell RNA-seq and machine learning. By functionally testing nearly 1,000 PsychENCODE enhancers, we identified more than 150 regulatory interactions, revealing enhancers that control key astrocyte functions and genes implicated in Al…

Golexanolone affords sustained microglia and astrocytes activation improvement in a rat model of Parkinson's disease.

INTRODUCTION: Golexanolone improves motor and non-motor alterations in the unilateral 6-OHDA rat model of PD. We hypothesized that a key mechanism by which golexanolone induces these beneficial effects is by reducing microglia activation, thus reducing pro-inflammatory factors (TNFα, IL-1α, HMGB1) which activate astrocytes. This work aims were to assess if golexanolone affords sustained improvement of glial activation and pro-inflammatory factors at 3 and 9 weeks after 6-OHDA injection. RESULTS: 6-OHDA rats show pro-inflammatory microglia in SN and striatum, with reduced area and increased TN…

The phenotypic transformation of astrocytes after AIS can be regulated by microglial GSDMD-mediated pyroptosis.

BACKGROUND: Microglial pyroptosis contributes to the pathogenesis of ischemic stroke through multiple pathways. However, it is unclear how it contributes to the phenotype switching of neuroinflammatory/ neuroprotective astrocytes. METHODS: This study established a mouse MCAO model and utilized microglial Gsdmd gene knockout mice to examine neuroinflammatory/neuroprotective astrocyte-related protein expression, infarct volume, mNSS scores, and other metrics. Additionally, a transwell co-culture model of microglia and astrocytes was constructed, followed by treatment with IL-1β, pyroptosis inhi…