scholarly journals Neuron-Derived Extracellular Vesicles Modulate Microglia Activation and Function

Biology ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 948
Author(s):  
Hui Peng ◽  
Brock T. Harvey ◽  
Christopher I. Richards ◽  
Kimberly Nixon
Keyword(s):  
Extracellular Vesicles ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Proinflammatory Response ◽  
Tnf Α ◽  
Rat Cortical Neurons ◽  
The Central Nervous System ◽  
And Function ◽  
And Control ◽  
Brain Homeostasis

Microglia act as the immune cells of the central nervous system (CNS). They play an important role in maintaining brain homeostasis but also in mediating neuroimmune responses to insult. The interactions between neurons and microglia represent a key process for neuroimmune regulation and subsequent effects on CNS integrity. However, the molecular mechanisms of neuron-glia communication in regulating microglia function are not fully understood. One recently described means of this intercellular communication is via nano-sized extracellular vesicles (EVs) that transfer a large diversity of molecules between neurons and microglia, such as proteins, lipids, and nucleic acids. To determine the effects of neuron-derived EVs (NDEVs) on microglia, NDEVs were isolated from the culture supernatant of rat cortical neurons. When NDEVs were added to primary cultured rat microglia, we found significantly improved microglia viability via inhibition of apoptosis. Additionally, application of NDEVs to cultured microglia also inhibited the expression of activation surface markers on microglia. Furthermore, NDEVs reduced the LPS-induced proinflammatory response in microglia according to reduced gene expression of proinflammatory cytokines (TNF-α, IL-6, MCP-1) and iNOS, but increased expression of the anti-inflammatory cytokine, IL-10. These findings support that neurons critically regulate microglia activity and control inflammation via EV-mediated neuron–glia communication. (Supported by R21AA025563 and R01AA025591).

scholarly journals MicroRNAs in the Neural Retina

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Kalina Andreeva ◽  
Nigel G. F. Cooper
Keyword(s):  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Neural Retina ◽  
Posttranscriptional Gene Regulation ◽  
Long Time ◽  
Gene Transcripts ◽  
The Central Nervous System ◽  
And Function ◽  
And Control

The health and function of the visual system rely on a collaborative interaction between diverse classes of molecular regulators. One of these classes consists of transcription factors, which are known to bind to DNA and control the transcription activities of their target genes. For a long time, it was thought that the transcription factors were the only regulators of gene expression. More recently, however, a novel class of regulators emerged. This class consists of a large number of small noncoding endogenous RNAs, namely, miRNAs. The miRNAs compose an essential component of posttranscriptional gene regulation, since they ultimately control the fate of gene transcripts. The retina, as a part of the central nervous system, is a well-established model for unraveling the molecular mechanisms underlying neuronal and glial functions. Numerous recent efforts have been made towards identification of miRNAs and their inferred roles in the visual pathway. In this review, we summarize the current state of our knowledge regarding the expression and function of miRNA in the neural retina and we discuss their potential uses as biomarkers for some retinal disorders.

scholarly journals Astrocyte- and Neuron-Derived Extracellular Vesicles from Alzheimer’s Disease Patients Effect Complement-Mediated Neurotoxicity

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1618 ◽  
Author(s):  
Carlos J. Nogueras-Ortiz ◽  
Vasiliki Mahairaki ◽  
Francheska Delgado-Peraza ◽  
Debamitra Das ◽  
Konstantinos Avgerinos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Viability ◽  
Extracellular Vesicles ◽  
Cortical Neurons ◽  
Membrane Attack Complex ◽  
Neurite Density ◽  
Complement Inhibitors ◽  
Rat Cortical Neurons ◽  
And Control

We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV/NEV uptake, as effectors of neurodegeneration in AD.

scholarly journals Astrocyte- and neuron-derived extracellular vesicles from Alzheimer’s disease patients effect complement-mediated neurotoxicity

2020 ◽  
Author(s):  
Carlos J Nogueras-Ortiz ◽  
Vasiliki Mahairaki ◽  
Francheska Delgado-Peraza ◽  
Debamitra Das ◽  
Konstantinos Avgerinos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Extracellular Vesicles ◽  
Cortical Neurons ◽  
Membrane Attack Complex ◽  
Neurite Density ◽  
Complement Inhibitors ◽  
Rat Cortical Neurons ◽  
And Control ◽  
Human Ipsc

AbstractWe have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurodegeneration, we assessed the neurotoxicity of immunocaptured AEVs (with anti-GLAST antibody), neuronal-origin NEVs (with anti-L1CAM antibody), and multicellular-origin (with anti-CD81 antibody) EVs from the plasma of AD, frontotemporal lobar degeneration (FTLD) and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons, membrane disruption, reduced neurite density, and decreased cell viability in rat cortical neurons and human IPSC-derived neurons. Neurodegenerative effects were not produced by multicellular-origin EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and suggest that neuronal MAC deposition is necessary for AEV/NEV-mediated neurodegeneration in AD.

Microglia extracellular vesicles: focus on molecular composition and biological function

2021 ◽  
Vol 49 (4) ◽  
pp. 1779-1790 ◽  
Author(s):  
Lorenzo Ceccarelli ◽  
Chiara Giacomelli ◽  
Laura Marchetti ◽  
Claudia Martini
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Biological Function ◽  
Biological Effects ◽  
Genetic Material ◽  
Cell Communication ◽  
Molecular Composition ◽  
Cargo Proteins ◽  
A Cell ◽  
The Central Nervous System

Extracellular vesicles (EVs) are a heterogeneous family of cell-derived lipid bounded vesicles comprising exosomes and microvesicles. They are potentially produced by all types of cells and are used as a cell-to-cell communication method that allows protein, lipid, and genetic material exchange. Microglia cells produce a large number of EVs both in resting and activated conditions, in the latter case changing their production and related biological effects. Several actions of microglia in the central nervous system are ascribed to EVs, but the molecular mechanisms by which each effect occurs are still largely unknown. Conflicting functions have been ascribed to microglia-derived EVs starting from the neuronal support and ending with the propagation of inflammation and neurodegeneration, confirming the crucial role of these organelles in tuning brain homeostasis. Despite the increasing number of studies reported on microglia-EVs, there is also a lot of fragmentation in the knowledge on the mechanism at the basis of their production and modification of their cargo. In this review, a collection of literature data about the surface and cargo proteins and lipids as well as the miRNA content of EVs produced by microglial cells has been reported. A special highlight was given to the works in which the EV molecular composition is linked to a precise biological function.

scholarly journals Serotonin Transporter Defect Disturbs Structure and Function of the Auditory Cortex in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Wenlu Pan ◽  
Jing Pan ◽  
Yan Zhao ◽  
Hongzheng Zhang ◽  
Jie Tang
Keyword(s):  
Auditory Cortex ◽  
Serotonin Transporter ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Frequency Tuning ◽  
Primary Auditory Cortex ◽  
Neuronal Morphology ◽  
Neuronal Connections ◽  
The Central Nervous System ◽  
And Function

Serotonin transporter (SERT) modulates the level of 5-HT and significantly affects the activity of serotonergic neurons in the central nervous system. The manipulation of SERT has lasting neurobiological and behavioral consequences, including developmental dysfunction, depression, and anxiety. Auditory disorders have been widely reported as the adverse events of these mental diseases. It is unclear how SERT impacts neuronal connections/interactions and what mechanism(s) may elicit the disruption of normal neural network functions in auditory cortex. In the present study, we report on the neuronal morphology and function of auditory cortex in SERT knockout (KO) mice. We show that the dendritic length of the fourth layer (L-IV) pyramidal neurons and the second-to-third layer (L-II/III) interneurons were reduced in the auditory cortex of the SERT KO mice. The number and density of dendritic spines of these neurons were significantly less than those of wild-type neurons. Also, the frequency-tonotopic organization of primary auditory cortex was disrupted in SERT KO mice. The auditory neurons of SERT KO mice exhibited border frequency tuning with high-intensity thresholds. These findings indicate that SERT plays a key role in development and functional maintenance of auditory cortical neurons. Auditory function should be examined when SERT is selected as a target in the treatment for psychiatric disorders.

Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical circuit assembly

2020 ◽  
Author(s):  
Yajun Xie ◽  
Aaron T. Kuan ◽  
Wengang Wang ◽  
Zachary T. Herbert ◽  
Olivia Mosto ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Critical Role ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Cortical Astrocytes ◽  
Functional Features ◽  
And Function ◽  
Circuit Assembly

SUMMARYNeuron-glia relationships play a critical role in the regulation of synapse formation and neuronal specification. The cellular and molecular mechanisms by which neurons and astrocytes communicate and coordinate are not well understood. Here we demonstrate that the canonical Sonic hedgehog (Shh) pathway is active in cortical astrocytes, where it acts to coordinate layer-specific synaptic connectivity and functional circuit development. We show that Ptch1 is a Shh receptor that is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of layer-specific astrocyte genes involved in regulating synapse formation and function. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses, moreover, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Together, these results suggest that Shh secreted from deep layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.

Renal NF-κB activation and TNF-α upregulation correlate with salt-sensitive hypertension in Dahl salt-sensitive rats

2006 ◽  
Vol 291 (6) ◽  
pp. R1817-R1824 ◽  
Author(s):  
Jian-Wei Gu ◽  
Niu Tian ◽  
Megan Shparago ◽  
Wei Tan ◽  
Amelia P. Bailey ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Molecular Mechanisms ◽  
Sodium Concentration ◽  
Interferon Γ ◽  
Binding Activity ◽  
Proinflammatory Response ◽  
Mobility Shift ◽  
Low Sodium Diet ◽  
Tnf Α

Molecular mechanisms of salt-sensitive (SS) hypertension related to renal inflammation have not been defined. We seek to determine whether a high-salt (HS) diet induces renal activation of NF-κB and upregulation of TNF-α related to the development of hypertension in Dahl SS rats. Six 8-wk-old male Dahl SS rats received a HS diet (4%), and six Dahl SS rats received a low-sodium diet (LS, 0.3%) for 5 wk. In the end, mean arterial pressure was determined in conscious rats by continuous monitoring through a catheter placed in the carotid artery. Mean arterial pressure was significantly higher in the HS than the LS group (177.9 ± 3.7 vs. 109.4 ± 2.9 mmHg, P < 0.001). There was a significant increase in urinary albumin secretion in the HS group compared with the LS group (22.3 ± 2.6 vs. 6.1 ± 0.7 mg/day; P < 0.001). Electrophoretic mobility shift assay demonstrated that the binding activity of NF-κB p65 proteins in the kidneys of Dahl SS rats was significantly increased by 53% in the HS group compared with the LS group ( P = 0.007). ELISA indicated that renal protein levels of TNF-α, but not IL-6, interferon-γ, and CCL28, were significantly higher in the HS than the LS group (2.3 ± 0.8 vs. 0.7 ± 0.2 pg/mg; P = 0.036). We demonstrated that plasma levels of TNF-α were significantly increased by fivefold in Dahl SS rats on a HS diet compared with a LS diet. Also, we found that increased physiologically relevant sodium concentration (10 mmol/l) directly stimulated NF-κB activation in cultured human renal proximal tubular epithelial cells. These findings support the hypothesis that activation of NF-κB and upregulation of TNF-α are the important renal mechanisms linking proinflammatory response to SS hypertension.

scholarly journals Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

2012 ◽  
Vol 87 (3) ◽  
pp. 1849-1860 ◽  
Author(s):  
Matthew F. Cusick ◽  
Jane E. Libbey ◽  
Dipan C. Patel ◽  
Daniel J. Doty ◽  
Robert S. Fujinami
Keyword(s):  
Proinflammatory Cytokines ◽  
Neuronal Excitability ◽  
Viral Infections ◽  
Cell Types ◽  
Proinflammatory Response ◽  
Necrosis Factor Alpha ◽  
Antiviral Immune Response ◽  
Acute Seizures ◽  
Tnf Α ◽  
The Central Nervous System

ABSTRACTViral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-α and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-α than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

scholarly journals Extracellular vesicles: Exosomes, microvesicles, and friends

2013 ◽  
Vol 200 (4) ◽  
pp. 373-383 ◽  
Author(s):  
Graça Raposo ◽  
Willem Stoorvogel
Keyword(s):  
Plasma Membrane ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Vesicle Release ◽  
Physiological Relevance ◽  
And Function ◽  
Extracellular Environment

Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.

scholarly journals Emerging Role for Epithelial Polarity Proteins of the Crumbs Family as Potential Tumor Suppressors

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Patrick Laprise
Keyword(s):  
Tumor Suppressors ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Tissue Growth ◽  
Epithelial Polarity ◽  
Mesenchymal Transition ◽  
Full Complement ◽  
Polarity Proteins ◽  
And Function ◽  
And Control

Defects in apical-basal polarity regulation are associated with tissue overgrowth and tumorogenesis, yet the molecular mechanisms linking epithelial polarity regulators to hyperplasia or neoplasia remain elusive. In addition, exploration of the expression and function of the full complement of proteins required for the polarized architecture of epithelial cells in the context of cancer is awaited. This paper provides an overview of recent studies performed onDrosophilaand vertebrates showing that apical polarity proteins of the Crumbs family act to repress tissue growth and epithelial to mesenchymal transition. Thus, these proteins emerge as potential tumor suppressors. Interestingly, analysis of the molecular function of Crumbs proteins reveals a function for these polarity regulators in junctional complexes stability and control of signaling pathways regulating proliferation and apoptosis. Thereby, these studies provide a molecular basis explaining how regulation of epithelial polarity is coupled to tumorogenesis.

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