Astrocytes

[Petr75]

2019 Dec 1
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University
McGill University, Montreal, Quebec, Canada
Astrocytes in the Pathogenesis of Multiple Sclerosis: An In Situ MicroRNA Study
https://www.ncbi.nlm.nih.gov/pubmed/31665376

Abstract
Astrocytes are increasingly recognized as active contributors to the disease process in multiple sclerosis (MS), rather than being merely reactive. We investigated the expression of a selected microRNA (miRNA) panel that could contribute both to the injury and to the recovery phases of the disease. Individual astrocytes were laser microdissected from brain sections. We then compared the miRNAs' expressions in MS and control brain samples at different lesional stages in white versus grey matter regions. In active MS lesions, we found upregulation of ischemia-related miRNAs in white but not grey matter, often with reversion to the normal state in inactive lesions. In contrast to our previous findings on MS macrophages, expression of 2 classical inflammatory-related miRNAs, miRNA-155 and miRNA-146a, was reduced in astrocytes from active and chronic active MS lesions in white and grey matter, suggesting a lesser direct pathogenetic role for these miRNAs in astrocytes. miRNAs within the categories regulating aquaporin4 (-100, -145, -320) and glutamate transport/apoptosis/neuroprotection (-124a, -181a, and -29a) showed some contrasting responses. The regional and lesion-stage differences of expression of these miRNAs indicate the remarkable ability of astrocytes to show a wide range of selective responses in the face of differing insults and phases of resolution.

[Petr75]

2019 Nov 26
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston
Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS
https://www.ncbi.nlm.nih.gov/pubmed/31813625

Abstract
Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.

[Petr75]

2020 Jan 25
Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway
Reactive Astrocytes as Therapeutic Targets for Brain Degenerative Diseases: Roles Played by Metabotropic Glutamate Receptors
https://pubmed.ncbi.nlm.nih.gov/3198300 ... receptors/

Abstract

Astrocytes are well known to play critical roles in the development and maintenance of the central nervous system (CNS). Moreover, recent reports indicate that these cells are heterogeneous with respect to the molecules they express and the functions they exhibit in the quiescent or activated state. Because astrocytes also contribute to pathology, promising new results raise the possibility of manipulating specific astroglial populations for therapeutic roles. In this mini-review, we highlight the function of metabotropic glutamate receptors (mGluRs), in particular mGluR3 and mGluR5, in reactive astrocytes and relate these to three degenerative CNS diseases: multiple sclerosis, Alzheimer's disease and Amyotrophic Lateral Sclerosis. Previous studies demonstrate that effects of these receptors may be beneficial, but this varies depending on the subtype of receptor, the state of the astrocytes, and the specific disease to which they are exposed. Elucidating the role of mGluRs on astrocytes at specific times during development and disease will provide novel insights in understanding how to best use these to serve as therapeutic targets.

[Petr75]

2020 Feb 12
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston
MAFG-driven Astrocytes Promote CNS Inflammation
https://pubmed.ncbi.nlm.nih.gov/3205159 ... lammation/


Abstract

Multiple sclerosis is a chronic inflammatory disease of the CNS1. Astrocytes contribute to the pathogenesis of multiple sclerosis2, but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.

[Petr75]

2020 Sep 30
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
Protective Functions of Reactive Astrocytes Following Central Nervous System Insult
https://pubmed.ncbi.nlm.nih.gov/33117368/

Abstract

Astrocytes play important roles in numerous central nervous system disorders including autoimmune inflammatory, hypoxic, and degenerative diseases such as Multiple Sclerosis, ischemic stroke, and Alzheimer's disease. Depending on the spatial and temporal context, activated astrocytes may contribute to the pathogenesis, progression, and recovery of disease. Recent progress in the dissection of transcriptional responses to varying forms of central nervous system insult has shed light on the mechanisms that govern the complexity of reactive astrocyte functions. While a large body of research focuses on the pathogenic effects of reactive astrocytes, little is known about how they limit inflammation and contribute to tissue regeneration. However, these protective astrocyte pathways might be of relevance for the understanding of the underlying pathology in disease and may lead to novel targeted approaches to treat autoimmune inflammatory and degenerative disorders of the central nervous system. In this review article, we have revisited the emerging concept of protective astrocyte functions and discuss their role in the recovery from inflammatory and ischemic disease as well as their role in degenerative disorders. Focusing on soluble astrocyte derived mediators, we aggregate the existing knowledge on astrocyte functions in the maintenance of homeostasis as well as their reparative and tissue-protective function after acute lesions and in neurodegenerative disorders. Finally, we give an outlook of how these mediators may guide future therapeutic strategies to tackle yet untreatable disorders of the central nervous system.

[Petr75]

2021 Sep
Neurobiology, Shanxi University of Chinese Medicine; Department of Neurology, Affiliated Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, China
Astrocytes: a double-edged sword in neurodegenerative diseases
https://pubmed.ncbi.nlm.nih.gov/33510058/

Abstract

Astrocytes play multifaceted and vital roles in maintaining neurophysiological function of the central nervous system by regulating homeostasis, increasing synaptic plasticity, and sustaining neuroprotective effects. Astrocytes become activated as a result of inflammatory responses during the progression of pathological changes associated with neurodegenerative disorders. Reactive astrocytes (neurotoxic A1 and neuroprotective A2) are triggered during disease progression and pathogenesis due to neuroinflammation and ischemia. However, only a limited body of literature describes morphological and functional changes of astrocytes during the progression of neurodegenerative diseases. The present review investigated the detrimental and beneficial roles of astrocytes in neurodegenerative diseases reported in recent studies, as these cells have promising therapeutic potential and offer new approaches for treatment of neurodegenerative diseases.

[NHE]

2021 Sep
Neurobiology, Shanxi University of Chinese Medicine; Department of Neurology, Affiliated Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, China
Astrocytes: a double-edged sword in neurodegenerative diseases
https://pubmed.ncbi.nlm.nih.gov/33510058/

Free full text: https://www.nrronline.org/temp/NeuralRe ... 090546.pdf



Figure 1: Reactive astrocytes in neurodegenerative diseases.
Astrocytes can be activated by multiple stimuli, particularly cytokines secreted by different cell types in the brain. In turn, activated astrocytes play a positive or negative role in multiple ways. (1) The blood-brain barrier (BBB) established by the end-feet of astrocytes, capillary endothelial cells, and basement membrane maintains homeostasis of the central nervous system. (2) Reactive astrocytes lose end-feet surrounding capillaries, resulting in damage to the BBB. Meanwhile, reactive astrocytes enhance the release of oxidants, cytokines, chemokines, and cell adhesion molecules, which can directly or indirectly damage oligodendrocyte precursor cells, oligodendrocytes, and neurons. (3) Vasoactive factors secreted by activated astrocytes affect normal endothelial cells by regulating junction-related proteins, which preserves the integrity of the BBB. Moreover, reactive astrocytes can promote remyelination and neuronal regeneration by secreting several growth factors