Astrocytes, a subtype of glial cells, come in variety of forms and functions. However, overarching role of these cell is in the homeostasis of the brain, be that regulation of ions, ...neurotransmitters, metabolism or neuronal synaptic networks. Loss of homeostasis represents the underlying cause of all brain disorders. Thus, astrocytes are likely involved in most if not all of the brain pathologies. We tabulate astroglial homeostatic functions along with pathological condition that arise from dysfunction of these glial cells. Classification of astrocytes is presented with the emphasis on evolutionary trails, morphological appearance and numerical preponderance. We note that, even though astrocytes from a variety of mammalian species share some common features, human astrocytes appear to be the largest and most complex of all astrocytes studied thus far. It is then an imperative to develop humanized models to study the role of astrocytes in brain pathologies, which is perhaps most abundantly clear in the case of glioblastoma multiforme.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Ageing is a key factor in the development of cognitive decline and dementia, an increasing and challenging problem of the modern world. The most commonly diagnosed cognitive decline is related to ...Alzheimer's disease (AD), the pathophysiology of which is poorly understood. Several hypotheses have been proposed. The cholinergic hypothesis is the oldest, however, recently the noradrenergic system has been considered to have a role as well. The aim of this review is to provide evidence that supports the view that an impaired noradrenergic system is causally linked to AD. Although dementia is associated with neurodegeneration and loss of neurons, this likely develops due to a primary failure of homeostatic cells, astrocytes, abundant and heterogeneous neuroglial cells in the central nervous system (CNS). The many functions that astrocytes provide to maintain the viability of neural networks include the control of ionic balance, neurotransmitter turnover, synaptic connectivity and energy balance. This latter function is regulated by noradrenaline, released from the axon varicosities of neurons arising from the locus coeruleus (LC), the primary site of noradrenaline release in the CNS. The demise of the LC is linked to AD, whereby a hypometabolic CNS state is observed clinically. This is likely due to impaired release of noradrenaline in the AD brain during states of arousal, attention and awareness. These functions controlled by the LC are needed for learning and memory formation and require activation of the energy metabolism. In this review, we address first the process of neurodegeneration and cognitive decline, highlighting the function of astrocytes. Cholinergic and/or noradrenergic deficits lead to impaired astroglial function. Then, we focus on adrenergic control of astroglial aerobic glycolysis and lipid droplet metabolism, which play a protective role but also promote neurodegeneration under some circumstances, supporting the noradrenergic hypothesis of cognitive decline. We conclude that targeting astroglial metabolism, glycolysis and/or mitochondrial processes may lead to important new developments in the future when searching for medicines to prevent or even halt cognitive decline.
Adrenergic regulation of astroglial aerobic glycolysis and lipid droplet (LD) metabolism in Alzheimer's disease. Noradrenaline (NA) is released form locus coeruleus axon varicosities which activates cyclic adenosine monophosphate (cAMP) production via β-adrenergic receptors (β-AR) in astrocytes, which stimulated glycogen breakdown via glycogen phosphorylase (GP). D-glucose phosphorylation via hexokinase is also stimulated by cAMP as is L-lactate production from pyruvate. NA in long term (prolonged stress condition) may by cAMP facilitate the accumulation and enlargement of LDs in astrocytes. Locus coeruleus demise during Alzheimer's disease may contribute to reduced levels of NA in the extracellular space in the CNS and consequently reduced astroglial export of L-lactate to the extracellular space, impairing also the L-lactate mediated enhancement of L-lactate production in astrocytes through a yet-unknown L-lactate receptor (LR) stimulating cAMP production (modified from (Horvat et al., 2021b)). Display omitted
•The demise of the locus coeruleus (LC) is linked to Alzheimers disease (AD).•Noradrenaline, released from the LC neurons, regulates astroglial energy provision for neurons.•In AD astrocyte energy regulation is impaired.•Astrocyte aerobic glycolysis represents a target for novel AD therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Astrocytes are housekeepers of the central nervous system (CNS) and are important for CNS development, homeostasis and defence. They communicate with neurones and other glial cells through the ...release of signalling molecules. Astrocytes secrete a wide array of classic neurotransmitters, neuromodulators and hormones, as well as metabolic, trophic and plastic factors, all of which contribute to the gliocrine system. The release of neuroactive substances from astrocytes occurs through several distinct pathways that include diffusion through plasmalemmal channels, translocation by multiple transporters and regulated exocytosis. As in other eukaryotic cells, exocytotic secretion from astrocytes involves divergent secretory organelles (synaptic‐like microvesicles, dense‐core vesicles, lysosomes, exosomes and ectosomes), which differ in size, origin, cargo, membrane composition, dynamics and functions. In this review, we summarize the features and functions of secretory organelles in astrocytes. We focus on the biogenesis and trafficking of secretory organelles and on the regulation of the exocytotic secretory system in the context of healthy and diseased astrocytes.
This review outlines the distinct secretory mechanism and organelles by which astrocytes secrete factors important for CNS development, homeostasis and cognitive function, as well as their contribution to health and diseases.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Astrocytes in Flavivirus Infections Potokar, Maja; Jorgačevski, Jernej; Zorec, Robert
International journal of molecular sciences,
02/2019, Volume:
20, Issue:
3
Journal Article
Peer reviewed
Open access
Virus infections of the central nervous system (CNS) can manifest in various forms of inflammation, including that of the brain (encephalitis) and spinal cord (myelitis), all of which may have ...long-lasting deleterious consequences. Although the knowledge of how different viruses affect neural cells is increasing, understanding of the mechanisms by which cells respond to neurotropic viruses remains fragmented. Several virus types have the ability to infect neural tissue, and astrocytes, an abundant and heterogeneous neuroglial cell type and a key element providing CNS homeostasis, are one of the first CNS cell types to get infected. Astrocytes are morphologically closely aligned with neuronal synapses, blood vessels, and ventricle cavities, and thereby have the capacity to functionally interact with neurons and endothelial cells. In this review, we focus on the responses of astrocytes to infection by neurotropic flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKV), West Nile virus (WNV), and Japanese encephalitis virus (JEV), which have all been confirmed to infect astrocytes and cause multiple CNS defects. Understanding these mechanisms may help design new strategies to better contain and mitigate virus- and astrocyte-dependent neuroinflammation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Ketamine, a general anaesthetic and psychotomimetic drug, exerts rapid, potent and long-lasting antidepressant effect, albeit the cellular and molecular mechanisms of this action are yet to be ...discovered. Besides targeting neuronal NMDARs fundamental for synaptic transmission, ketamine affects the function of astroglia the key homeostatic cells of the central nervous system that contribute to pathophysiology of psychiatric diseases including depression. Here we review studies revealing that (sub)anaesthetic doses of ketamine elevate intracellular cAMP concentration (cAMPi) in astrocytes, attenuate stimulus-evoked astrocyte calcium signalling, which regulates exocytotic secretion of gliosignalling molecules, and stabilize the vesicle fusion pore in a narrow configuration possibly hindering cargo discharge or vesicle recycling. Next we discuss how ketamine affects astroglial capacity to control extracellular K+ by reducing cytoplasmic mobility of vesicles delivering the inward rectifying potassium channel (Kir4.1) to the plasmalemma. Modified astroglial K+ buffering impacts upon neuronal excitability as demonstrated in the lateral habenula rat model of depression. Finally, we highlight the recent discovery that ketamine rapidly redistributes cholesterol in the plasmalemma of astrocytes, but not in fibroblasts nor in neuronal cells. This alteration of membrane structure may modulate a host of processes that synergistically contribute to ketamine's rapid and prominent antidepressant action.
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•Ketamine inhibits calcium signalling and enhances cAMP production in astroglia.•Ketamine suppresses exocytosis of gliosignalling molecules and Kir4.1.•Ketamine elevates cholesterol content in the plasmalemma specifically in astrocytes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • The enteric nervous system (ENS) is the largest assembly of neurons and glia outside the central nervous system. • The ENS resides within the wall of the digestive tract and regulates ...local gut reflexes involved in gastrointestinal motility, blood flow and fluid transport. • Enteric glial cells are necessary and sufficient to modulate neuronal reflex circuits controlling gut motility. • Enteric glia respond to various neurotransmitters via increase in intracellular calcium and release of neuroactive substances, such as ATP through Cx43 hemichannels or Ca2+ -dependent exocytosis. • Enteric glial cells are actively involved in gut motility disorders and regulation of inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Gliotransmitters are chemicals released from glial cells fulfilling a following set of criteria: (i) they are synthesized by and/or stored in glia; (ii) their regulated release is triggered ...by physiological and/or pathological stimuli; (iii) they activate rapid (milliseconds to seconds) responses in neighboring cells; and (iv) they play a role in (patho)physiological processes. Astrocytes can release a variety of gliotransmitters into the extracellular space using several different mechanisms. In this review, we focus on exocytotic mechanism(s) underlying the release of three classes of gliotransmitters: (i) amino acids, such as, glutamate and d -serine; (ii) nucleotides, like adenosine 5′-triphosphate; and (iii) peptides, such as, atrial natriuretic peptide and brain-derived neurotrophic factor. It is becoming clear that astrocytes are endowed with elements that qualify them as cells communicating with neurons and other cells within the central nervous system by employing regulated exocytosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Impairment of the main noradrenergic nucleus of the human brain, the locus coeruleus (LC), which has been discovered in 1784, represents one of defining factors of neurodegenerative diseases ...progression. Projections of LC neurons release noradrenaline/norepinephrine (NA), which stimulates astrocytes, homeostatic neuroglial cells enriched with adrenergic receptors. There is a direct correlation between the reduction in noradrenergic innervations and cognitive decline associated with ageing and neurodegenerative diseases. It is, therefore, hypothesized that the resilience of LC neurons to degeneration influences the neural reserve that in turn determines cognitive decline. Deficits in the noradrenergic innervation of the brain might be reversed or restrained by increasing the activity of existing LC neurons, transplanting noradrenergic neurons, and/or using drugs that mimic the activity of NA on astroglia. Here, these strategies are discussed with the aim to understand how astrocytes integrate neuronal network activity in the brain information processing in health and disease.
Astrocytes are the target of noradrenergic innervation in the adult brain. Activation of astroglial adrenergic receptors trigger intracellular signals mediated by Ca2+ or second messengers, which control astroglial homeostatic cascades that contribute to the maintenance of cognitive reserve. Deficits in adrenergic innervation may disrupt astroglial function and exacerbate cognitive abnormalities.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Astrocyte Aquaporin Dynamics in Health and Disease Potokar, Maja; Jorgačevski, Jernej; Zorec, Robert
International Journal of Molecular Sciences,
07/2016, Volume:
17, Issue:
7
Journal Article, Book Review
Peer reviewed
Open access
The family of aquaporins (AQPs), membrane water channels, consists of diverse types of proteins that are mainly permeable to water; some are also permeable to small solutes, such as glycerol and ...urea. They have been identified in a wide range of organisms, from microbes to vertebrates and plants, and are expressed in various tissues. Here, we focus on AQP types and their isoforms in astrocytes, a major glial cell type in the central nervous system (CNS). Astrocytes have anatomical contact with the microvasculature, pia, and neurons. Of the many roles that astrocytes have in the CNS, they are key in maintaining water homeostasis. The processes involved in this regulation have been investigated intensively, in particular regulation of the permeability and expression patterns of different AQP types in astrocytes. Three aquaporin types have been described in astrocytes: aquaporins AQP1 and AQP4 and aquaglyceroporin AQP9. The aim here is to review their isoforms, subcellular localization, permeability regulation, and expression patterns in the CNS. In the human CNS, AQP4 is expressed in normal physiological and pathological conditions, but astrocytic expression of AQP1 and AQP9 is mainly associated with a pathological state.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Astrocytes play an important housekeeping role in the central nervous system. Additionally, as secretory cells, they actively participate in cell‐to‐cell communication, which can be mediated by ...membrane‐bound vesicles. The gliosignaling molecules stored in these vesicles are discharged into the extracellular space after the vesicle membrane fuses with the plasma membrane. This process is termed exocytosis, regulated by SNARE proteins, and triggered by elevations in cytosolic calcium levels, which are necessary and sufficient for exocytosis in astrocytes. For astrocytic exocytosis, calcium is sourced from the intracellular endoplasmic reticulum store, although its entry from the extracellular space contributes to cytosolic calcium dynamics in astrocytes. Here, we discuss calcium management in astrocytic exocytosis and the properties of the membrane‐bound vesicles that store gliosignaling molecules, including the vesicle fusion machinery and kinetics of vesicle content discharge. In astrocytes, the delay between the increase in cytosolic calcium activity and the discharge of secretions from the vesicular lumen is orders of magnitude longer than that in neurons. This relatively loose excitation‐secretion coupling is likely tailored to the participation of astrocytes in modulating neural network processing. GLIA 2016;64:655–667
Main points
In comparison to neurons, vesicle‐based secretion of gliosignaling molecules from astrocytes occurs with a delay to the stimulus.
This property places astrocytes as signal integrators responding to slow‐based signaling processes in the brain.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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