Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

Chen, Miaomiao; Lai, Xing-Ning; Wang, Xifeng; Ying, Jun; Zhang, Lieliang; Zhou, Bin; Liu, Xing; Zhang, Jing; Wei, Gen; Hua, Fuzhou

doi:10.3389/fnmol.2021.745066

Cited by 69 publications

(38 citation statements)

References 152 publications

(209 reference statements)

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“…The classical activation is related to pro-inflammatory cytokine production, such as tumor necrosis factor-α ( TNF- α), interleukin-1β ( IL-1 β) and reactive oxygen species (ROS) or nitric oxide (NO) production. Meanwhile, the alternative activation promotes anti-inflammatory response with increased IL-4, IL-10, CD36 and phagocytic response expressing CD163, insulin-like growth factor 1 (IGF-1) and brain derived neurotrophic factor (BDNF) ( Le et al, 2016 ; Chen et al, 2021 ; Figure 1 ). The microglial polarization has not been supported by single-cell RNA-seq, while this transcriptomic analysis have been used to distinguish between diseased associated microglia (DAM) or activated response microglia (ARM) ( Keren-Shaul et al, 2017 ; Sala Frigerio et al, 2019 ).…”

Section: Microglial Activation In Alzheimer’s Diseasementioning

confidence: 99%

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Revuelta

Urrutia

Villarroel

et al. 2022

Front. Cell. Neurosci.

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Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer’s Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid β peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-α, IL-1β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase KV1.3 channels expression, protein levels and current density. Several studies highlight the importance of KV1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid β accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that KV1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1β and TNF-α through the NF-kB and p38MAPK pathway. Overall, we conclude that KV1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients.

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Section: Microglial Activation In Alzheimer’s Diseasementioning

confidence: 99%

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Revuelta

Urrutia

Villarroel

et al. 2022

Front. Cell. Neurosci.

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“…All of the continuously accumulating data suggest that various non-coding RNA species and the so-called "competing endogenous RNA network” (the detailed reporting of which is unfortunately well beyond the scope of this article, for very extensive literature and a review on the matter see [ 446 , 447 , 448 , 449 ]) might contribute to MS pathogenesis via several already known and yet to be discovered pathways and mechanisms. Circular RNAs are prominent members of this family onto whom intense research has been focused in recent years.…”

Section: Fluid Biomarkers Of Multiple Sclerosismentioning

confidence: 99%

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: A Focus on Neurofilaments and Therapeutic Considerations

Biernacki

Kokas

Sandi

et al. 2022

IJMS

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Introduction: Multiple Sclerosis (MS) is the most common immune-mediated chronic neurodegenerative disease of the central nervous system (CNS) affecting young people. This is due to the permanent disability, cognitive impairment, and the enormous detrimental impact MS can exert on a patient’s health-related quality of life. It is of great importance to recognise it in time and commence adequate treatment at an early stage. The currently used disease-modifying therapies (DMT) aim to reduce disease activity and thus halt disability development, which in current clinical practice are monitored by clinical and imaging parameters but not by biomarkers found in blood and/or the cerebrospinal fluid (CSF). Both clinical and radiological measures routinely used to monitor disease activity lack information on the fundamental pathophysiological features and mechanisms of MS. Furthermore, they lag behind the disease process itself. By the time a clinical relapse becomes evident or a new lesion appears on the MRI scan, potentially irreversible damage has already occurred in the CNS. In recent years, several biomarkers that previously have been linked to other neurological and immunological diseases have received increased attention in MS. Additionally, other novel, potential biomarkers with prognostic and diagnostic properties have been detected in the CSF and blood of MS patients. Areas covered: In this review, we summarise the most up-to-date knowledge and research conducted on the already known and most promising new biomarker candidates found in the CSF and blood of MS patients. Discussion: the current diagnostic criteria of MS relies on three pillars: MRI imaging, clinical events, and the presence of oligoclonal bands in the CSF (which was reinstated into the diagnostic criteria by the most recent revision). Even though the most recent McDonald criteria made the diagnosis of MS faster than the prior iteration, it is still not an infallible diagnostic toolset, especially at the very early stage of the clinically isolated syndrome. Together with the gold standard MRI and clinical measures, ancillary blood and CSF biomarkers may not just improve diagnostic accuracy and speed but very well may become agents to monitor therapeutic efficacy and make even more personalised treatment in MS a reality in the near future. The major disadvantage of these biomarkers in the past has been the need to obtain CSF to measure them. However, the recent advances in extremely sensitive immunoassays made their measurement possible from peripheral blood even when present only in minuscule concentrations. This should mark the beginning of a new biomarker research and utilisation era in MS.

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“…In this study, an OGD/R cell model was constructed to investigate the microarray of astrocyte-derived exosomes, their effect on apoptosis and transformation of microglia phenotypes. Moreover, based on the miRNA-seq analysis, literature research ( 27 ), and bioinformatic study, a crucial LncRNA–microRNA–mRNA axis that regulates the course of acute systemic ischemia/reperfusion injury was identified. By gain-of-function and loss-of-function experiments, we specifically examined how the LncRNA GAS5/miR-137/INPP4B axis is involved in the OGD/R-stimulated astrocyte–microglia crosstalk.…”

Section: Introductionmentioning

confidence: 99%

LncRNA GAS5/miR-137 Is a Hypoxia-Responsive Axis Involved in Cardiac Arrest and Cardiopulmonary Cerebral Resuscitation

et al. 2022

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BackgroundCardiac arrest/cardiopulmonary resuscitation (CA/CPR) represents one of the devastating medical emergencies and is associated with high mortality and neuro-disability. Post-cardiac arrest syndrome (PCAS) is mechanistically ascribed to acute systemic ischemia/reperfusion(I/R) injury. The lncRNA/microRNA/mRNA networks have been found to play crucial roles in the pathogenesis of the hypoxia-responsive diseases. Nonetheless, the precise molecular mechanisms by which lncRNA/miRNA/mRNA axes are involved in the astrocyte–microglia crosstalk in CA/CPR have not been fully elucidated.MethodsWe collected and purified the exosomes from the blood of CA/CPR patients and supernatant of OGD/R-stimulated astrocytes. On the basis of microarray analysis, bioinformatic study, and luciferase activity determination, we speculated that lncRNA GAS5/miR-137 is implicated in the astrocyte–microglia crosstalk under the insult of systemic I/R injury. The regulation of lncRNA GAS5/miR-137 on INPP4B was examined by cellular transfection in OGD/R cell culture and by lateral ventricle injection with miR-137 agomir in CA/CPR mice model. Flow cytometry and immunofluorescence staining were performed to detect the microglial apoptosis, M1/M2 phenotype transformation, and neuroinflammation. Neurological scoring and behavior tests were conducted in CA/CPR group, with miR-137 agomir lateral-ventricle infusion and in their controls.ResultsIn all the micRNAs, miR-137 was among the top 10 micRNAs that experienced greatest changes, in both the blood of CA/CPR patients and supernatant of OGD/R-stimulated astrocytes. Bioinformatic analysis revealed that miR-137 was sponged by lncRNA GAS5, targeting INPP4B, and the result was confirmed by Luciferase activity assay. qRT-PCR and Western blotting showed that lncRNA GAS5 and INPP4B were over-expressed whereas miR-137 was downregulated in the blood of CA/CPR patients, OGD/R-stimulated astrocytes, and brain tissue of CA/CPR mice. Silencing lncRNA GAS5 suppressed INPP4B expression, but over-expression of miR-137 negatively modulated its expression. Western blotting exhibited that PI3K and Akt phosphorylation was increased when lncRNA GAS5 was silenced or miR-137 was over-expressed. However, PI3K and Akt phosphorylation was notably suppressed in the absence of miR-137, almost reversing their phosphorylation in the silencing lncRNA GAS5 group. Then we found that GAS5 siRNA or miR-137 mimic significantly increased cell viability and alleviated apoptosis after OGD/R injury. Furthermore, over-expression of miR-137 attenuated microglial apoptosis and neuroinflammation in CA/CPR mice model, exhibiting significantly better behavioral tests after CA/CPR.ConclusionLncRNA GAS5/miR-137 may be involved in the astrocyte–microglia communication that inhibits PI3K/Akt signaling activation via regulation of INPP4B during CA/CPR.

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Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

Cited by 69 publications

References 152 publications

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: A Focus on Neurofilaments and Therapeutic Considerations

LncRNA GAS5/miR-137 Is a Hypoxia-Responsive Axis Involved in Cardiac Arrest and Cardiopulmonary Cerebral Resuscitation

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