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1.
J Neuroimmune Pharmacol ; 19(1): 8, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427092

RESUMO

Aberrant activation of complement cascades plays an important role in the progress of neurological disorders. Complement C3, the central complement component, has been implicated in synaptic loss and cognitive impairment. Recent study has shown that wound injury-induced systemic inflammation can trigger the increase of C3 in the brain. Our previous studies have demonstrated that laparotomy-triggered systemic inflammation could induce neuroinflammation and cognitive dysfunctions. Furthermore, sustained activation of microglia was observed even 14 days after laparotomy, while most of cytokines had returned to basal levels rapidly at the earlier time point. Although we have demonstrated that anti-inflammatory intervention successfully attenuated cognitive dysfunction by preventing increase of cytokines and activation of microglia, how sustained activation of microglia and cognitive dysfunction occur is still a mystery. In this study, we investigated the role of C3 in mediating activation of microglia and cognitive dysfunction by using laparotomy in adult male mouse only as the experimental model of systemic inflammation and AAV9-C3shRNA. Our data observed that laparotomy induced neurotoxic reactive astrocytes with an increase of C3 in the hippocampus. Furthermore, inhibition of C3 by AAV9-C3shRNA prevented synaptic engulfment by microglia and attenuated cognitive dysfunctions after laparotomy. Inhibition of C3 did not modulate activation of astrocytes and expression of various cytokines. Current findings demonstrated that C3 plays significant roles in sustained activation of microglia and cognitive dysfunctions, which suggests that C3 is the valuable molecule target to attenuate in neurological conditions characterised by neuroinflammation and cognitive dysfunction.


Assuntos
Disfunção Cognitiva , Complemento C3 , Animais , Masculino , Camundongos , Astrócitos/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Laparotomia/efeitos adversos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Doenças Neuroinflamatórias
2.
Sci Prog ; 107(1): 368504241231154, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38425276

RESUMO

The underlying mechanisms for the beneficial effects exerted by bone marrow-mesenchymal stem cells (BM-MSCs) in treating repetitive traumatic brain injury (rTBI)-induced long-term sensorimotor/cognitive impairments are not fully elucidated. Herein, we aimed to explore whether BM-MSCs therapy protects against rTBI-induced long-term neurobehavioral disorders in rats via normalizing white matter integrity and gray matter microglial response. Rats were subjected to repeated mild lateral fluid percussion on day 0 and day 3. On the fourth day post-surgery, MSCs groups received MSCs (4 × 106 cells/ml/kg, intravenously) and were assessed by the radial maze, Y maze, passive avoidance tests, and modified neurological severity scores. Hematoxylin & eosin, and Luxol fast blue stainings were used to examine the histopathology and white matter thickness. At the same time, immunofluorescence staining was used to investigate the numbers of tumor necrosis factor-alpha (TNF-α)-containing microglia in gray matter. Three to nine months after neurotrauma, rats displayed sensorimotor and cognitive impairments, reduced thickness in white matter, and over-accumulation of TNF-α-containing microglia and cellular damage in gray matter. Therapy with BM-MSCs significantly attenuated the rTBI-induced sensorimotor and cognitive impairments and all their complications. Mesenchymal stem cell therapy might accelerate the recovery of sensorimotor and cognitive impairments in rats with rTBI via normalizing myelin integrity and microglia response.


Assuntos
Lesões Encefálicas Traumáticas , Disfunção Cognitiva , Células-Tronco Mesenquimais , Ratos , Animais , Bainha de Mielina , Microglia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologia , Lesões Encefálicas Traumáticas/terapia , Cognição
3.
Methods Mol Biol ; 2785: 177-193, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427195

RESUMO

This paper provides an overview of the role of neuroinflammation in Alzheimer's disease and other neurodegenerative diseases, highlighting the potential of anti-inflammatory treatments to slow or prevent decline. This research focuses on the use of positron emission tomography (PET) imaging to visualize and quantify molecular brain changes in patients, specifically microglial activation and reactive astrogliosis. We discuss the development and application of several PET radioligands, including first-generation ligands like PK11195 and Ro5-4864, as well as second- and third-generation ligands such as [11C]PBR28, [18F]DPA-714, [18F]GE-180, and [11C]ER176. These ligands target the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia and upregulated in astrocytes. We also address the limitations of these ligands, such as low brain uptake, poor penetration of the blood-brain barrier, short half-life, and variable kinetic behavior. Furthermore, we demonstrate the impact of genetic polymorphisms on ligand binding.


Assuntos
Doença de Alzheimer , Doenças Neuroinflamatórias , Humanos , Receptores de GABA/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Doença de Alzheimer/metabolismo , Ligantes , Microglia/metabolismo
4.
Methods Mol Biol ; 2761: 231-243, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427240

RESUMO

Microglia are scavengers of the brain environment that clear dead cells, debris, and microbes. In Alzheimer's disease, microglia get activated to phagocytose damaged neurons, extracellular Amyoid-ß, and Tau deposits. Several Tau internalization mechanisms of microglia have been studied which include phagocytosis, pinocytosis, and receptor-mediated endocytosis. In this chapter, we have visualized microglial phagocytic structures that are actin-rich cup-like extensions, which surrounds extracellular Tau species by wide-field fluorescence and confocal microscopy. We have shown the association of filamentous actin in Tau phagocytosis along the assembly of LC-3 molecules to phagosomes. The 3-dimensional, orthogonal and gallery wise representation of these phagocytic structures provides an overview of the phagocytic mechanism of extracellular Tau by microglia.


Assuntos
Doença de Alzheimer , Microglia , Humanos , Microglia/metabolismo , Actinas , Fagocitose/fisiologia , Transporte Biológico , Peptídeos beta-Amiloides/metabolismo
5.
Methods Mol Biol ; 2761: 245-255, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427241

RESUMO

Alzheimer's disease (AD) is distinguished by extracellular accumulation of amyloid-beta plaques and intracellular neurofibrillary tangles of Tau. Pathogenic Tau species are also known to display "prion-like propagation," which explains their presence in extracellular spaces as well. Glial population, especially microglia, tend to proclaim neuroinflammatory condition, disrupted signaling mechanisms, and cytoskeleton deregulation in AD. Omega-3 fatty acids play a neuroprotective role in the brain, which can trigger the anti-inflammatory pathways as well as actin dynamics in the cells. Improvement of cytoskeletal assembly mechanism by omega-3 fatty acids would regulate the other signaling cascades in the cells, leading to refining clearance of extracellular protein burden in AD. In this study, we focused on analyzing the ability of α-linolenic acid (ALA) as a regulator of actin dynamics to balance the signaling pathways in microglia, including endocytosis of extracellular Tau burden in AD.


Assuntos
Doença de Alzheimer , Ácido alfa-Linolênico , Humanos , Ácido alfa-Linolênico/farmacologia , Ácido alfa-Linolênico/metabolismo , Proteínas tau/metabolismo , Actinas/metabolismo , Microglia/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo
6.
Adv Neurobiol ; 36: 149-172, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38468031

RESUMO

Microglia and neurons live physically intertwined, intimately related structurally and functionally in a dynamic relationship in which microglia change continuously over a much shorter timescale than do neurons. Although microglia may unwind and depart from the neurons they attend under certain circumstances, in general, together both contribute to the fractal topology of the brain that defines its computational capabilities. Both neuronal and microglial morphologies are well-described using fractal analysis complementary to more traditional measures. For neurons, the fractal dimension has proved valuable for classifying dendritic branching and other neuronal features relevant to pathology and development. For microglia, fractal geometry has substantially contributed to classifying functional categories, where, in general, the more pathological the biological status, the lower the fractal dimension for individual cells, with some exceptions, including hyper-ramification. This chapter provides a review of the intimate relationships between neurons and microglia, by introducing 2D and 3D fractal analysis methodology and its applications in neuron-microglia function in health and disease.


Assuntos
Fractais , Microglia , Humanos , Neurônios/fisiologia , Encéfalo
7.
Mol Neurodegener ; 19(1): 24, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468308

RESUMO

Microglia are highly dynamic cells that play a critical role in tissue homeostasis through the surveillance of brain parenchyma and response to cues associated with damage. Aging and APOE4 genotype are the strongest risk factors for Alzheimer's disease (AD), but how they affect microglial dynamics remains unclear. Using ex vivo confocal microscopy, we analyzed microglial dynamic behaviors in the entorhinal cortex (EC) and hippocampus CA1 of 6-, 12-, and 21-month-old mice APOE3 or APOE4 knock-in mice expressing GFP under the CX3CR1 promoter. To study microglia surveillance, we imaged microglia baseline motility for 20 min and measured the extension and retraction of processes. We found that APOE4 microglia exhibited significantly less brain surveillance (27%) compared to APOE3 microglia in 6-month-old mice; aging exacerbated this deficit. To measure microglia response to damage, we imaged process motility in response to ATP, an injury-associated signal, for 30 min. We found APOE4 microglia extended their processes significantly slower (0.9 µm/min, p < 0.005) than APOE3 microglia (1.1 µm/min) in 6-month-old animals. APOE-associated alterations in microglia motility were observed in 12- and 21-month-old animals, and this effect was exacerbated with aging in APOE4 microglia. We measured protein and mRNA levels of P2RY12, a core microglial receptor required for process movement in response to damage. We found that APOE4 microglia express significantly less P2RY12 receptors compared to APOE3 microglia despite no changes in P2RY12 transcripts. To examine if the effect of APOE4 on the microglial response to ATP also applied to amyloid ß (Aß), we infused locally Hi-Lyte Fluor 555-labeled Aß in acute brain slices of 6-month-old mice and imaged microglia movement for 2 h. APOE4 microglia showed a significantly slower (p < 0.0001) process movement toward the Aß, and less Aß coverage at early time points after Aß injection. To test whether P2RY12 is involved in process movement in response to Aß, we treated acute brain slices with a P2RY12 antagonist before Aß injection; microglial processes no longer migrated towards Aß. These results provide mechanistic insights into the impact of APOE4 genotype and aging in dynamic microglial behaviors prior to gross Aß pathology and could help explain how APOE4 brains are more susceptible to AD pathogenesis.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Animais , Camundongos , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Genótipo , Camundongos Transgênicos , Microglia/metabolismo
8.
Int J Nanomedicine ; 19: 2265-2284, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38476273

RESUMO

Introduction: Glaucoma is a prevalent cause of irreversible vision impairment, characterized by progressive retinal ganglion cells (RGCs) loss, with no currently available effective treatment. Rapamycin (RAPA), an autophagy inducer, has been reported to treat glaucoma in rodent models by promoting RGC survival, but its limited water solubility, systemic toxicity, and pre-treatment requirements hinder its potential clinical applications. Methods: Chitosan (CS)-RAPA carbon dot (CRCD) was synthesized via hydrothermal carbonization of CS and RAPA and characterized by transmission electron microscopy, Fourier transform infrared spectra, and proton nuclear magnetic resonance. In vitro assays on human umbilical cord vein endothelial and rat retinal cell line examined its biocompatibility and anti-oxidative capabilities, while lipopolysaccharide-stimulated murine microglia (BV2) assays measured its effects on microglial polarization. In vivo, using a mouse retinal ischemia/reperfusion (I/R) model by acute intraocular pressure elevation, the effects of CRCD on visual function, RGC apoptosis, oxidative stress, and M2 microglial polarization were examined. Results: CRCD exhibited good water solubility and anti-oxidative capabilities, in the form of free radical scavenging. In vitro, CRCD was bio-compatible and lowered oxidative stress, which was also found in vivo in the retinal I/R model. Additionally, both in vitro with lipopolysaccharide-stimulated BV2 cells and in vivo with the I/R model, CRCD was able to promote M2 microglial polarization by activating autophagy, which, in turn, down-regulated pro-inflammatory cytokines, such as IL-1ß and TNF-α, as well as up-regulated anti-inflammatory cytokines, such as IL-4 and TGF-ß. All these anti-oxidative and anti-inflammatory effects ultimately aided in preserving RGCs, and subsequently, improved visual function. Discussion: CRCD could serve as a potential novel treatment strategy for glaucoma, via incorporating RAPA into CDs, in turn not only mitigating its toxic side effects but also enhancing its therapeutic efficacy.


Assuntos
Quitosana , Glaucoma , Traumatismo por Reperfusão , Ratos , Animais , Camundongos , Humanos , Microglia/patologia , Quitosana/farmacologia , Sirolimo/farmacologia , Carbono/farmacologia , Lipopolissacarídeos/farmacologia , Glaucoma/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Autofagia , Citocinas/metabolismo , Água , Traumatismo por Reperfusão/tratamento farmacológico
9.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473822

RESUMO

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer's Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk.


Assuntos
Doença de Alzheimer , Humanos , Animais , Camundongos , Microglia , Proteínas Amiloidogênicas , Precursor de Proteína beta-Amiloide , Mutação , Placa Amiloide , Presenilina-1 , Peptídeos beta-Amiloides , Camundongos Transgênicos , Modelos Animais de Doenças
10.
Cells ; 13(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38474350

RESUMO

Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight, and cell death. Alterations in the sole output of the cerebellar cortex, Purkinje cells, and central nervous system immune cells, microglia, have been reported in animal models of FASD. To determine how developmental ethanol exposure affects adult cerebellar microglia and Purkinje cells, we used a human third-trimester binge exposure model in which mice received ethanol or saline from postnatal (P) days 4-9. In adolescence, cerebellar cranial windows were implanted and mice were aged to young adulthood for examination of microglia and Purkinje cells in vivo with two-photon imaging or in fixed tissue. Ethanol had no effect on microglia density, morphology, dynamics, or injury response. However, Purkinje cell linear frequency was reduced by ethanol. Microglia-Purkinje cell interactions in the Purkinje Cell Layer were altered in females compared to males. Overall, developmental ethanol exposure had few effects on cerebellar microglia in young adulthood and Purkinje cells appeared to be more susceptible to its effects.


Assuntos
Etanol , Transtornos do Espectro Alcoólico Fetal , Gravidez , Masculino , Humanos , Feminino , Animais , Camundongos , Adulto Jovem , Adulto , Idoso , Etanol/farmacologia , Células de Purkinje , Transtornos do Espectro Alcoólico Fetal/etiologia , Transtornos do Espectro Alcoólico Fetal/metabolismo , Microglia/metabolismo , Cerebelo/metabolismo , Modelos Animais de Doenças
11.
J Neuroinflammation ; 21(1): 67, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38481312

RESUMO

Tissue-resident macrophages play an important role in the local maintenance of homeostasis and immune surveillance. In the central nervous system (CNS), brain macrophages are anatomically divided into parenchymal microglia and non-parenchymal border-associated macrophages (BAMs). Among these immune cell populations, microglia have been well-studied for their roles during development as well as in health and disease. BAMs, mostly located in the choroid plexus, meningeal and perivascular spaces, are now gaining increased attention due to advancements in multi-omics technologies and genetic methodologies. Research on BAMs over the past decade has focused on their ontogeny, immunophenotypes, involvement in various CNS diseases, and potential as therapeutic targets. Unlike microglia, BAMs display mixed origins and distinct self-renewal capacity. BAMs are believed to regulate neuroimmune responses associated with brain barriers and contribute to immune-mediated neuropathology. Notably, BAMs have been observed to function in diverse cerebral pathologies, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, ischemic stroke, and gliomas. The elucidation of the heterogeneity and diverse functions of BAMs during homeostasis and neuroinflammation is mesmerizing, since it may shed light on the precision medicine that emphasizes deep insights into programming cues in the unique brain immune microenvironment. In this review, we delve into the latest findings on BAMs, covering aspects like their origins, self-renewal capacity, adaptability, and implications in different brain disorders.


Assuntos
Doenças do Sistema Nervoso Central , Sistema Nervoso Central , Humanos , Sistema Nervoso Central/patologia , Macrófagos/patologia , Microglia/patologia , Encéfalo/patologia
12.
J Mol Neurosci ; 74(1): 30, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478195

RESUMO

Microglia are resident macrophages within the central nervous system, serving as the first responders to neuroinflammation. Glucocorticoids (GCs) may cause damage to brain tissue, but the specific mechanism remains unclear. This study was divided into two parts: a glucocorticoid receptor (GR) mitochondrial translocation intervention experiment and a mitochondrial oxidative stress inhibition experiment. BV-2 microglia were stimulated with dexamethasone (DEX) and treated with either tubastatin-A or mitoquinone (MitoQ) for 24 h. Our results showed that DEX increased the translocation of GRs to mitochondria, and this effect was accompanied by decreases in the expression of mitochondrially encoded cytochrome c oxidase 1 (MT-CO1) and mitochondrially encoded cytochrome c oxidase 3 (MT-CO3) and increases in the expression of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), caspase-1, and Gasdermin D (GSDMD). The level of mitochondrial respiratory chain complex IV (MRCC IV) and adenosine triphosphate (ATP) was decreased. An elevation in the level of mitochondrial oxidative stress and the opening of the mitochondrial permeability transition pore (mPTP) was also observed. Mechanistically, tubastatin-A significantly suppressed the mitochondrial translocation of GRs, improved the expression of mitochondrial genes, promoted the restoration of mitochondrial function, and inhibited pyroptosis. MitoQ significantly prevented mitochondrial oxidative stress, improved mitochondrial function, and reduced apoptosis and pyroptosis. Both tubastatin-A and MitoQ suppressed DEX-induced pyroptosis. This study substantiates that the increase in the mitochondrial translocation of GRs mediated by GCs exacerbates oxidative stress and pyroptosis in microglia, which indicates that the regulation of mitochondrial pathways by GCs is pathogenic to microglia.


Assuntos
Glucocorticoides , Piroptose , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Microglia/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Estresse Oxidativo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
13.
Immunity ; 57(3): 401-403, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38479354

RESUMO

Exploring the mechanisms of microglia activation has revealed insights into the interconnections of the immune system and brain. Huang et al. demonstrate that the complex of sodium/potassium-transporting ATPase subunit alpha (NKAα1) and purinergic P2X7 receptor (P2X7R) maintains the resting state of microglial membranes. Stress increases free P2X7R that then binds to ATP to activate microglia, which may promote anxious behaviors.


Assuntos
Doenças Neuroinflamatórias , Receptores Purinérgicos P2X7 , Humanos , Receptores Purinérgicos P2X7/metabolismo , Microglia/metabolismo , Encéfalo/metabolismo , Trifosfato de Adenosina/metabolismo
14.
CNS Neurosci Ther ; 30(3): e14674, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38468130

RESUMO

BACKGROUND: Long-term non-traumatic noise exposure, such as heavy traffic noise, can elicit emotional disorders in humans. However, the underlying neural substrate is still poorly understood. METHODS: We exposed mice to moderate white noise for 28 days to induce anxiety-like behaviors, measured by open-field, elevated plus maze, and light-dark box tests. In vivo multi-electrode recordings in awake mice were used to examine neuronal activity. Chemogenetics were used to silence specific brain regions. Viral tracing, immunofluorescence, and confocal imaging were applied to define the neural circuit and characterize the morphology of microglia. RESULTS: Exposure to moderate noise for 28 days at an 85-dB sound pressure level resulted in anxiety-like behaviors in open-field, elevated plus maze, and light-dark box tests. Viral tracing revealed that fibers projecting from the auditory cortex and auditory thalamus terminate in the lateral amygdala (LA). A noise-induced increase in spontaneous firing rates of the LA and blockade of noise-evoked anxiety-like behaviors by chemogenetic inhibition of LA glutamatergic neurons together confirmed that the LA plays a critical role in noise-induced anxiety. Noise-exposed animals were more vulnerable to anxiety induced by acute noise stressors than control mice. In addition to these behavioral abnormalities, ionized calcium-binding adaptor molecule 1 (Iba-1)-positive microglia in the LA underwent corresponding morphological modifications, including reduced process length and branching and increased soma size following noise exposure. Treatment with minocycline to suppress microglia inhibited noise-associated changes in microglial morphology, neuronal electrophysiological activity, and behavioral changes. Furthermore, microglia-mediated synaptic phagocytosis favored inhibitory synapses, which can cause an imbalance between excitation and inhibition, leading to anxiety-like behaviors. CONCLUSIONS: Our study identifies LA microglial activation as a critical mediator of noise-induced anxiety-like behaviors, leading to neuronal and behavioral changes through selective synapse phagocytosis. Our results highlight the pivotal but previously unrecognized roles of LA microglia in chronic moderate noise-induced behavioral changes.


Assuntos
Ansiedade , Microglia , Humanos , Camundongos , Animais , Ansiedade/etiologia , Ansiedade/psicologia , Neurônios , Sinapses , Tonsila do Cerebelo
15.
CNS Neurosci Ther ; 30(3): e14666, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38468126

RESUMO

AIM: To explore the neuroprotective potential of hyperforin and elucidate its underlying molecular mechanisms involved in its therapeutic effects against vascular cognitive impairment (VCI). METHODS: The active compounds and possible targets of Hypericum perforatum L. that may be effective against VCI were found by network pharmacology in this research. We utilized bilateral common carotid artery occlusion (BCCAO) surgery to induce a VCI mouse model. Morris water maze (MWM) and Y-maze tests were used to assess VCI mice's cognitive abilities following treatment with hyperforin. To evaluate white matter lesions (WMLs), we utilized Luxol fast blue (LFB) stain and immunofluorescence (IF). Neuroinflammation was assessed using IF, western blot (WB), and enzyme-linked immunosorbent assay (ELISA). The effects of hyperforin on microglia were investigated by subjecting the BV2 microglial cell line to oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The expressions of VEGFR2 , p-SRC, SRC, VEGFA, and inflammatory markers including IL-10, IL-1ß, TNF-α, and IL-6 were subsequently assessed. RESULTS: The VEGFR2 /SRC signaling pathway is essential for mediating the protective properties of hyperforin against VCI according to network pharmacology analysis. In vivo findings demonstrated that hyperforin effectively improved BCCAO-induced cognitive impairment. Furthermore, staining results showed that hyperforin attenuated WMLs and reduced microglial activation in VCI mice. The hyperforin treatment group's ELISA results revealed a substantial decrease in IL-1ß, IL-6, and TNF-α levels. According to the results of in vitro experiments, hyperforin decreased the release of pro-inflammatory mediators (TNF-α, IL-6, and IL-1ß) and blocked microglial M1-polarization by modulating the VEGFR2 /SRC signaling pathway. CONCLUSION: Hyperforin effectively modulated microglial M1 polarization and neuroinflammation by inhibiting the VEGFR2 /SRC signaling pathways, thereby ameliorating WMLs and cognitive impairment in VCI mice.


Assuntos
Disfunção Cognitiva , Floroglucinol/análogos & derivados , Terpenos , Substância Branca , Camundongos , Animais , Microglia , Doenças Neuroinflamatórias , Fator de Necrose Tumoral alfa/metabolismo , Substância Branca/metabolismo , Interleucina-6/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo
16.
Int J Mol Sci ; 25(5)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38473758

RESUMO

Alzheimer's disease (AD) is the most common form of dementia, characterized by the accumulation of ß-amyloid plaques, tau tangles, neuroinflammation, and synaptic/neuronal loss, the latter being the strongest correlating factor with memory and cognitive impairment. Through an in vitro study on a neurons-astrocytes-microglia (NAM) co-culture system, we analyzed the effects of cerebrospinal fluid (CSF) samples from AD and non-AD patients (other neurodegenerative pathologies). Treatment with CSF from AD patients showed a loss of neurofilaments and spheroids, suggesting the presence of elements including CX3CL1 (soluble form), destabilizing the neurofilaments, cellular adhesion processes, and intercellular contacts. The NAM co-cultures were analyzed in immunofluorescence assays for several markers related to AD, such as through zymography, where the expression of proteolytic enzymes was quantified both in cell extracts and the co-cultures' conditioned medium (CM). Through qRT-PCR assays, several genes involved in the formation of ß-amyloid plaque, in phosphorylation of tau, and in inflammation pathways and MMP expression were investigated.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Microglia/metabolismo , Técnicas de Cocultura , Astrócitos/metabolismo , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo
17.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473794

RESUMO

MicroRNAs (miRs) act as important post-transcriptional regulators of gene expression in glial cells and have been shown to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we investigated the effects of agathisflavone, a biflavonoid purified from the leaves of Cenostigma pyramidale (Tul.), on modulating the expression of miRs and inflammatory mediators in activated microglia. C20 human microglia were exposed to oligomers of the ß-amyloid peptide (Aß, 500 nM) for 4 h or to lipopolysaccharide (LPS, 1 µg/mL) for 24 h and then treated or not with agathisflavone (1 µM) for 24 h. We observed that ß-amyloid and LPS activated microglia to an inflammatory state, with increased expression of miR-146a, miR-155, IL1-ß, IL-6, and NOS2. Treatment with agathisflavone resulted in a significant reduction in miR146a and miR-155 induced by LPS or Aß, as well as inflammatory cytokines IL1-ß, IL-6, and NOS2. In cells stimulated with Aß, there was an increase in p-STAT3 expression that was reduced by agathisflavone treatment. These data identify a role for miRs in the anti-inflammatory effect of agathisflavone on microglia in models of neuroinflammation and AD.


Assuntos
Doença de Alzheimer , Biflavonoides , MicroRNAs , Humanos , Biflavonoides/farmacologia , Microglia/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Citocinas/metabolismo , MicroRNAs/genética , Fator de Transcrição STAT3/metabolismo
18.
Int J Mol Sci ; 25(5)2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38473954

RESUMO

This experimental study was designed to evaluate the effect of ulinastatin, a urinary trypsin inhibitor, on postoperative cognitive dysfunction (POCD) in rats under general anesthesia with isoflurane, on the aspect of behavior, as evaluated using a Y-maze test and focusing on microglial activity. Ulinastatin (50,000 U/mL) and normal saline (1 mL) were randomly (1:1) administered intraperitoneally to the ulinastatin and control groups, respectively, before general anesthesia. Anesthesia with isoflurane 1.5 volume% was maintained for 2 h. The Y-maze test was used to evaluate cognitive function. Neuronal damage using caspase-1 expression, the degree of inflammation through cytokine detection, and microglial activation with differentiation of the phenotypic expression were evaluated. Twelve rats were enrolled in the study and evenly allocated into the two groups, with no dropouts from the study. The Y-maze test showed similar results in the two groups before general anesthesia (63 ± 12% in the control group vs. 64 ± 12% in the ulinastatin group, p = 0.81). However, a significant difference was observed between the two groups after general anesthesia (17 ± 24% in the control group vs. 60 ± 12% in the ulinastatin group, p = 0.006). The ulinastatin group showed significantly lower expression of caspase-1. Pro-inflammatory cytokine levels were significantly lower in the ulinastatin group than in the control group. The ulinastatin group had a significantly lower microglial activation (41.74 ± 10.56% in the control group vs. 4.77 ± 0.56% in the ulinastatin, p < 0.001), with a significantly lower activation of M1 phenotypes (52.19 ± 7.83% in the control group vs. 5.58 ± 0.76% in the ulinastatin group, p < 0.001). Administering ulinastatin before general anesthesia prevented neuronal damage and cognitive decline after general anesthesia, in terms of the aspect of behavior, as evaluated by the Y-maze test. The protective effect of ulinastatin was associated with the inhibition of microglial activation, especially the M1 phenotype.


Assuntos
Disfunção Cognitiva , Glicoproteínas , Isoflurano , Complicações Cognitivas Pós-Operatórias , Ratos , Animais , Isoflurano/farmacologia , Microglia , Citocinas/farmacologia , Caspase 1 , Aprendizagem em Labirinto , Inibidores da Tripsina/farmacologia
19.
Cells ; 13(5)2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38474371

RESUMO

Toll-like receptors (TLRs) are a collection of pattern recognition sensors that form a first line of defence by detecting pathogen- or damage-associated molecular patterns and initiating an inflammatory response. TLR activation in microglia, the major immune cells in the brain, can trigger the release of inflammatory molecules, which may contribute to various CNS diseases including Alzheimer's disease. Recently, some microRNAs were shown to serve as signalling molecules for TLRs. Here, we present miR-154-5p as a novel TLR7 ligand. Exposing microglia to miR-154-5p results in cytokine release and alters expression of the TLR signalling pathway dependent on TLR7. Additionally, miR-154-5p causes neuronal injury in enriched cortical neuron cultures and additive toxicity in the presence of microglia. Finally, intrathecal injection of miR-154-5p into mice leads to neuronal injury and accumulation of microglia in the cerebral cortex dependent on TLR7 expression. In conclusion, this study establishes miR-154-5p as a direct activator of TLR7 that can cause neuroinflammation and neuronal injury, which may contribute to CNS disease.


Assuntos
MicroRNAs , Microglia , Receptor 7 Toll-Like , Animais , Camundongos , Ligantes , Microglia/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Receptor 7 Toll-Like/metabolismo , Humanos
20.
Exp Biol Med (Maywood) ; 249: 10120, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38463392

RESUMO

Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.


Assuntos
MicroRNAs , Doenças do Sistema Nervoso , Humanos , Doenças Neuroinflamatórias , Doenças do Sistema Nervoso/genética , Microglia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Citocinas/metabolismo , Quimiocinas/metabolismo
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