Pathological remodeling of reactive astrocytes: Involvement of DNA methylation and downregulation of homeostatic genes.

Astrocytes provide metabolic support to neurons, maintain ionic and water homeostasis, and uptake and recycle neurotransmitters. After exposure to the prototypical PAMP lipopolysaccharide (LPS), reactive astrocytes increase the expression of pro-inflammatory genes, facilitating neurodegeneration. In this study, we analyzed the expression of homeostatic genes in astrocytes exposed to LPS and identified the epigenetic factors contributing to the suppression of homeostatic genes in reactive astrocytes.

Nucleophosmin 1 cooperates with the methyltransferase DOT1L to preserve peri-nucleolar heterochromatin organization by regulating H3K27me3 levels and DNA repeats expression.

Background: NPM1 is a phosphoprotein highly abundant in the nucleolus. However, additional nuclear functions have been attributed to NPM1, probably through interaction with other nuclear factors. DOT1L is one interaction partner of NPM1 that catalyzes methylation of histone H3 at lysine 79 (H3K79).

Progression of reactive gliosis and astroglial phenotypic changes following stab wound-induced traumatic brain injury in mice.

Astrocytes are the main homeostatic cells in the central nervous system (CNS) and they have an essential role in preserving neuronal physiology. After brain injury, astrocytes become reactive, and that involves a profound change in the astroglial gene expression program as well as intense cytoskeleton remodeling that has been classically shown by the up-regulation of glial fibrillary acidic protein (GFAP), a pan-reactive gene over-expressed in reactive astrocytes, independently of the type of injury. Using the stab wound rodent model of penetrating traumatic injury in the cortex, we here studied the reactive astroglial morphology and reactive microgliosis in detail at 1, 3, 7, 14, and 28 days post-injury (dpi).

Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome.

Forkhead box G1 (FOXG1) has important functions in neuronal differentiation and balances excitatory/inhibitory network activity. Thus far, molecular processes underlying FOXG1 function are largely unexplored. Here, we present a multiomics data set exploring how FOXG1 impacts neuronal maturation at the chromatin level in the mouse hippocampus.

Early life stress induces visual dysfunction and retinal structural alterations in adult mice.

Early life stress (ELS) is defined as a period of severe and/or chronic trauma, as well as environmental/social deprivation or neglect in the prenatal/early postnatal stage. Presently, the impact of ELS on the retina in the adult stage is unknown. The long-term consequences of ELS at retinal level were analyzed in an animal model of maternal separation with early weaning (MSEW), which mimics early life maternal neglect.

Pathological Neuroinflammatory Conversion of Reactive Astrocytes Is Induced by Microglia and Involves Chromatin Remodeling.

Following brain injury or in neurodegenerative diseases, astrocytes become reactive and may suffer pathological remodeling, features of which are the loss of their homeostatic functions and a pro-inflammatory gain of function that facilitates neurodegeneration. Pharmacological intervention to modulate this astroglial response and neuroinflammation is an interesting new therapeutic research strategy, but it still requires a deeper understanding of the underlying cellular and molecular mechanisms of the phenomenon. Based on the known microglial-astroglial interaction, the prominent role of the nuclear factor kappa B (NF-κB) pathway in mediating astroglial pathological pro-inflammatory gain of function, and its ability to recruit chromatin-remodeling enzymes, we first explored the microglial role in the initiation of astroglial pro-inflammatory conversion and then monitored the progression of epigenetic changes in the astrocytic chromatin.

Different Flavors of Astrocytes: Revising the Origins of Astrocyte Diversity and Epigenetic Signatures to Understand Heterogeneity after Injury.

Astrocytes are a specific type of neuroglial cells that confer metabolic and structural support to neurons. Astrocytes populate all regions of the nervous system and adopt a variety of phenotypes depending on their location and their respective functions, which are also pleiotropic in nature. For example, astrocytes adapt to pathological conditions with a specific cellular response known as reactive astrogliosis, which includes extensive phenotypic and transcriptional changes.

Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders?

With confirmed coronavirus disease 2019 (COVID-19) cases surpassing the 18 million mark around the globe, there is an imperative need to gain comprehensive understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the main clinical manifestations of COVID-19 are associated with respiratory or intestinal symptoms, reports of neurological signs and symptoms are increasing. The etiology of these neurological manifestations remains obscure, and probably involves several direct pathways, not excluding the direct entry of the virus to the central nervous system (CNS) through the olfactory epithelium, circumventricular organs, or disrupted blood-brain barrier.

Detrimental Effects of HMGB-1 Require Microglial-Astroglial Interaction: Implications for the Status Epilepticus -Induced Neuroinflammation.

Temporal Lobe Epilepsy (TLE) is the most common form of human epilepsy and available treatments with antiepileptic drugs are not disease-modifying therapies. The neuroinflammation, neuronal death and exacerbated plasticity that occur during the silent period, following the initial precipitating event (IPE), seem to be crucial for epileptogenesis. Damage Associated Molecular Patterns (DAMP) such as HMGB-1, are released early during this period concomitantly with a phenomenon of reactive gliosis and neurodegeneration.

TGFβ-Signaling and FOXG1-Expression Are a Hallmark of Astrocyte Lineage Diversity in the Murine Ventral and Dorsal Forebrain.

Heterogeneous astrocyte populations are defined by diversity in cellular environment, progenitor identity or function. Yet, little is known about the extent of the heterogeneity and how this diversity is acquired during development. To investigate the impact of TGF (transforming growth factor) β-signaling on astrocyte development in the telencephalon we deleted the TGFBR2 (transforming growth factor beta receptor 2) in early neural progenitor cells in mice using a FOXG1 (forkhead box G1)-driven CRE-recombinase.

FOXG1 Regulates PRKAR2B Transcriptionally and Posttranscriptionally via miR200 in the Adult Hippocampus.

Rett syndrome is a complex neurodevelopmental disorder that is mainly caused by mutations in MECP2. However, mutations in FOXG1 cause a less frequent form of atypical Rett syndrome, called FOXG1 syndrome. FOXG1 is a key transcription factor crucial for forebrain development, where it maintains the balance between progenitor proliferation and neuronal differentiation.

DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex.

Cortical development is controlled by transcriptional programs, which are orchestrated by transcription factors. Yet, stable inheritance of spatio-temporal activity of factors influencing cell fate and localization in different layers is only partly understood. Here we find that deletion of Dot1l in the murine telencephalon leads to cortical layering defects, indicating DOT1L activity and chromatin methylation at H3K79 impact on the cell cycle, and influence transcriptional programs conferring upper layer identity in early progenitors.

Toll-Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) Activation Balance Astrocyte Polarization into a Proinflammatory Phenotype.

Astrocytes react to brain injury with a generic response known as reactive gliosis, which involves activation of multiple intracellular pathways including several that may be beneficial for neuronal survival. However, by unknown mechanisms, reactive astrocytes can polarize into a proinflammatory phenotype that induces neurodegeneration. In order to study reactive gliosis and astroglial polarization into a proinflammatory phenotype, we used cortical devascularization-induced brain ischemia in Wistar rats and primary astroglial cell cultures exposed to oxygen-glucose deprivation (OGD).

Isolation and Characterization of Ischemia-Derived Astrocytes (IDAs) with Ability to Transactivate Quiescent Astrocytes.

Unlabelled: Reactive gliosis involving activation and proliferation of astrocytes and microglia, is a widespread but largely complex and graded glial response to brain injury. Astroglial population has a previously underestimated high heterogeneity with cells differing in their morphology, gene expression profile, and response to injury. Here, we identified a subset of reactive astrocytes isolated from brain focal ischemic lesions that show several atypical characteristics.

DOT1L Activity Promotes Proliferation and Protects Cortical Neural Stem Cells from Activation of ATF4-DDIT3-Mediated ER Stress In Vitro.

Growing evidence suggests that the lysine methyltransferase DOT1L/KMT4 has important roles in proliferation, survival, and differentiation of stem cells in development and in disease. We investigated the function of DOT1L in neural stem cells (NSCs) of the cerebral cortex. The pharmacological inhibition and shRNA-mediated knockdown of DOT1L impaired proliferation and survival of NSCs.

The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

Sleep apnea (SA) causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH) experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA.

S100B protein activates a RAGE-dependent autocrine loop in astrocytes: implications for its role in the propagation of reactive gliosis.

Extracellular S100B dramatically increases after brain injury. While low S100B levels are neuroprotective, micromolar S100B levels have shown in vitro to activate microglia and facilitate neuronal death. In astrocytes, S100B exposure activates nuclear factor kappa B (NF-κB) and induces pro-inflammatory mediators.

Gabapentin administration reduces reactive gliosis and neurodegeneration after pilocarpine-induced status epilepticus.

The lithium-pilocarpine model of epilepsy reproduces in rodents several features of human temporal lobe epilepsy, by inducing an acute status epilepticus (SE) followed by a latency period. It has been proposed that the neuronal network reorganization that occurs during latency determines the subsequent appearance of spontaneous recurrent seizures. The aim of this study was to evaluate neuronal and glial responses during the latency period that follows SE.

Manganese induces mitochondrial dynamics impairment and apoptotic cell death: a study in human Gli36 cells.

Manganese (Mn) is an essential trace element due to its participation in many physiological processes. However, overexposure to this metal leads to a neurological disorder known as Manganism whose clinical manifestations and molecular mechanisms resemble Parkinson's disease. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity being the mitochondria the most affected organelles.

S100B alters neuronal survival and dendrite extension via RAGE-mediated NF-κB signaling.

S100B is a soluble protein secreted by astrocytes that exerts pro-survival or pro-apoptotic effects depending on the concentration reached in the extracellular millieu. The S100B receptor termed RAGE (for receptor for advanced end glycation products) is highly expressed in the developing brain but is undetectable in normal adult brain. In this study, we show that RAGE expression is induced in cortical neurons of the ischemic penumbra.

Intermittent hypoxia during sleep induces reactive gliosis and limited neuronal death in rats: implications for sleep apnea.

Sleep apnea (SA) can be effectively managed in humans but it is recognized that when left untreated, SA causes long-lasting changes in neuronal circuitry in the brain. Recent neuroimaging studies gave suggested that these neuronal changes are also present even in patients successfully treated for the acute effects of SA. The cellular mechanisms that account for these changes are not certain but animal models of intermittent hypoxia (IH) during sleep have shown neuronal death and impairment in learning and memory.

p75 NTR expression is induced in isolated neurons of the penumbra after ischemia by cortical devascularization.

The p75 neurotrophin receptor (p75(NTR)) is involved in neuronal functions ranging from induction of apoptosis and growth inhibition to the promotion of survival. p75(NTR) expression is induced in the central nervous system (CNS) by a range of pathological conditions, where it seems to have a role in neuronal death and axonal growth inhibition. The cellular mechanisms driving p75(NTR) expression in cell lines and primary neurons is Sp1 dependent (Ramos et al.