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1.
Nat Commun ; 11(1): 4966, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009404

RESUMO

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults, with an unknown etiology. A hallmark of TLE is the characteristic loss of layer 3 neurons in the medial entorhinal area (MEA) that underlies seizure development. One approach to intervention is preventing loss of these neurons through better understanding of underlying pathophysiological mechanisms. Here, we show that both neurons and glia together give rise to the pathology that is mitigated by the amino acid D-serine whose levels are potentially diminished under epileptic conditions. Focal administration of D-serine to the MEA attenuates neuronal loss in this region thereby preventing epileptogenesis in an animal model of TLE. Additionally, treatment with D-serine reduces astrocyte counts in the MEA, alters their reactive status, and attenuates proliferation and/or infiltration of microglia to the region thereby curtailing the deleterious consequences of neuroinflammation. Given the paucity of compounds that reduce hyperexcitability and neuron loss, have anti-inflammatory properties, and are well tolerated by the brain, D-serine, an endogenous amino acid, offers new hope as a therapeutic agent for refractory TLE.


Assuntos
Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/patologia , Serina/uso terapêutico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Comportamento Animal , Encéfalo/patologia , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/patologia , Gliose/patologia , Inflamação/patologia , Microglia/efeitos dos fármacos , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos Sprague-Dawley , Serina/administração & dosagem , Serina/farmacologia
2.
Proc Natl Acad Sci U S A ; 117(39): 24464-24474, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32929007

RESUMO

Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus [MHV], strain JHMV), we show that depletion of microglia during the time of JHMV clearance resulted in impaired myelin repair and prolonged clinical disease without affecting the kinetics of virus clearance. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Furthermore, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial functions affected by depletion could not be compensated by infiltrating macrophages. Together, these results demonstrate that microglia play key roles in debris clearance and in the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.


Assuntos
Infecções por Coronavirus/patologia , Doenças Desmielinizantes/patologia , Microglia/patologia , Remielinização , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Imunidade Celular/efeitos dos fármacos , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Vírus da Hepatite Murina/efeitos dos fármacos , Vírus da Hepatite Murina/fisiologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Oligodendroglia/patologia , Compostos Orgânicos/administração & dosagem , Compostos Orgânicos/efeitos adversos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Remielinização/genética , Medula Espinal/imunologia , Medula Espinal/patologia
3.
Acta Neuropathol Commun ; 8(1): 147, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847628

RESUMO

We document the neuropathologic findings of a 73-year old man who died from acute cerebellar hemorrhage in the context of relatively mild SARS-CoV2 infection. The patient developed sudden onset of headache, nausea, and vomiting, immediately followed by loss of consciousness on the day of admission. Emergency medical services found him severely hypoxemic at home, and the patient suffered a cardiac arrest during transport to the emergency department. The emergency team achieved return of spontaneous circulation after over 17 min of resuscitation. A chest radiograph revealed hazy bilateral opacities; and real-time-PCR for SARS-CoV-2 on the nasopharyngeal swab was positive. Computed tomography of the head showed a large right cerebellar hemorrhage, with tonsillar herniation and intraventricular hemorrhage. One day after presentation, he was transitioned to comfort care and died shortly after palliative extubation. Autopsy performed 3 h after death showed cerebellar hemorrhage and acute infarcts in the dorsal pons and medulla. Remarkably, there were microglial nodules and neuronophagia bilaterally in the inferior olives and multifocally in the cerebellar dentate nuclei. This constellation of findings has not been reported thus far in the context of SARS-CoV-2 infection.


Assuntos
Infartos do Tronco Encefálico/patologia , Doenças Cerebelares/patologia , Infecções por Coronavirus/patologia , Hemorragias Intracranianas/patologia , Microglia/patologia , Neurônios/patologia , Fagocitose , Pneumonia Viral/patologia , Idoso , Betacoronavirus , Infartos do Tronco Encefálico/complicações , Infartos do Tronco Encefálico/diagnóstico por imagem , Doenças Cerebelares/complicações , Doenças Cerebelares/diagnóstico por imagem , Núcleos Cerebelares/patologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Cefaleia/etiologia , Parada Cardíaca/etiologia , Humanos , Hipóxia/etiologia , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/diagnóstico por imagem , Masculino , Bulbo/diagnóstico por imagem , Bulbo/patologia , Núcleo Olivar/patologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Tegmento Pontino/diagnóstico por imagem , Tegmento Pontino/patologia , Tomografia Computadorizada por Raios X
5.
Int J Nanomedicine ; 15: 4919-4932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764925

RESUMO

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Diagnosing AD before symptoms arise will facilitate earlier intervention. The early diagnostic approaches are thus urgently needed. Methods: The multifunctional nanoparticles W20/XD4-SPIONs were constructed by the conjugation of oligomer-specific scFv antibody W20 and class A scavenger receptor (SR-A) activator XD4 onto superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs' stability and uniformity in size were measured by dynamic light scattering and transmission electron microscopy. The ability of W20/XD4-SPIONs for recognizing Aß oligomers (AßOs) and promoting AßOs phagocytosis was assessed by immunocytochemistry and flow cytometry analysis. The blood-brain barrier permeability of W20/XD4-SPIONs was determined by a co-culture transwell model. The in vivo probe distribution of W20/XD4-SPIONs in AD mouse brains was detected by magnetic resonance imaging (MRI). Results: W20/XD4-SPIONs, as an AßOs-targeted molecular MRI contrast probe, readily reached pathological AßOs regions in brains and distinguished AD transgenic mice from WT controls. W20/XD4-SPIONs retained the property of XD4 for SR-A activation and significantly promoted microglial phagocytosis of AßOs. Moreover, W20/XD4-SPIONs exhibited the properties of good biocompatibility, high stability and low cytotoxicity. Conclusion: Compared with W20-SPIONs or XD4-SPIONs, W20/XD4-SPIONs show the highest efficiency for AßOs-targeting and significantly enhance AßOs uptake by microglia. As a molecular probe, W20/XD4-SPIONs also specifically and sensitively bind to AßOs in AD brains to provide an MRI signal, demonstrating that W20/XD4-SPIONs are promising diagnostic agents for early-stage AD. Due to the beneficial effect of W20 and XD4 on neuropathology, W20/XD4-SPIONs may also have therapeutic potential for AD .


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/imunologia , Imunoconjugados/química , Nanopartículas de Magnetita/química , Receptores Depuradores/metabolismo , Anticorpos de Cadeia Única/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Especificidade de Anticorpos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Diagnóstico Precoce , Imunoconjugados/farmacologia , Imagem por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Nanopartículas Multifuncionais/química , Fagocitose/efeitos dos fármacos , Anticorpos de Cadeia Única/imunologia
6.
J Thorac Cardiovasc Surg ; 160(2): e55-e66, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689704

RESUMO

OBJECTIVES: This study aims to evaluate the protective effects of progesterone on white matter injury and brain immaturity in neonatal rats with chronic hypoxia. METHODS: Three-day old Sprague-Dawley rats were randomly divided into 3 groups: (1) control (n = 48), rats were exposed to normoxia (fraction of inspired oxygen: 21% ± 0%); (2) chronic hypoxia (n = 48), rats were exposed to hypoxia (fraction of inspired oxygen: 10.5% ± 1.0%); and (3) progesterone (n = 48), rats were exposed to hypoxia and administrated with progesterone (8 mg/kg/d). Hematoxylin-eosin staining, immunohistochemistry, real-time quantitative polymerase chain reaction, and Western blot analyses were compared on postnatal day 14 in different groups. Motor skill and coordination abilities of rats were assessed via rotation experiments. RESULTS: Increased brain weights (P < .05), narrowed ventricular sizes (P < .01), and rotarod experiment scores (P < .01) were better in the progesterone group than in the chronic hypoxia group. The number of mature oligodendrocytes and myelin basic protein expression increased in the progesterone group compared with the chronic hypoxia group (P < .01). The polarization of M1 microglia cells in the corpus callosum of chronic hypoxia-induced hypomyelination rats was significantly increased, whereas there were fewer M2 microglia cells. Conversely, progesterone therapy had an opposite effect and caused an increase in M2 microglia polarization versus a reduction in M1 microglia cells. CONCLUSIONS: Progesterone could prevent white matter injury and improve brain maturation in a neonatal hypoxic rat model; this may be associated with inducing a switch from M1 to M2 in microglia.


Assuntos
Encéfalo/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Leucoencefalopatias/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Substância Branca/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Plasticidade Celular/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Feminino , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/fisiopatologia , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos Sprague-Dawley , Substância Branca/metabolismo , Substância Branca/patologia , Substância Branca/fisiopatologia
7.
Nature ; 582(7810): 89-94, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483373

RESUMO

A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3-9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6-9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics-as well as transplanting gut microflora from a protective environment-attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.


Assuntos
Proteína C9orf72/genética , Microbioma Gastrointestinal/fisiologia , Gliose/microbiologia , Gliose/patologia , Inflamação/genética , Inflamação/microbiologia , Medula Espinal/patologia , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Antibacterianos/farmacologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , Autoimunidade/imunologia , Movimento Celular/efeitos dos fármacos , Citocinas/imunologia , Transplante de Microbiota Fecal , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Gliose/genética , Gliose/prevenção & controle , Inflamação/patologia , Inflamação/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Camundongos , Microglia/imunologia , Microglia/microbiologia , Microglia/patologia , Medula Espinal/imunologia , Medula Espinal/microbiologia , Taxa de Sobrevida
8.
Life Sci ; 256: 117894, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502544

RESUMO

AIMS: Pathological alterations in the brain can cause microglial activation (MA). Thus, inhibiting MA could provide a new approach for treating neurodegenerative disorders. MAIN METHODS: To investigate the effect of C16 peptide and angiopoietin-1 (Ang1) on inflammation following MA, we stimulated microglial BV-2 cells with lipopolysaccharide (LPS) and used dexmedetomidine (DEX) as a positive control. Specific inhibitors of Tie2, αvß3 and α5ß1 integrins, and PI3K/Akt were applied to investigate the neuron-protective and anti-inflammatory effects and signaling pathway of C16 + Ang1 treatment in the LPS-induced BV-2 cells. KEY FINDINGS: Our results showed that C16 + Ang1 treatment reduced the microglia M1 phenotype but promoted the microglia M2 phenotype. In addition, C16 + Ang1 treatment suppressed leukocyte migration across human pulmonary microvascular endothelial cells, reduced the levels of pro-inflammatory factors [inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß, tumor necrosis factor (TNF-α)], and cellular apoptosis factors (caspase-3 and p53), and decreased lactate dehydrogenase (LDH) release, but promoted anti-inflammatory cytokine (IL-10) expression and cell proliferation in the LPS-activated BV-2 cells. The signaling pathways underlying the neuron-protective and anti-inflammatory effects of C16 + Ang1 may be mediated by Tie2-PI3K/Akt, Tie2-integrin and integrin-PI3K/Akt. SIGNIFICANCE: The neuron-protective and anti-inflammatory effects of C16 + Ang1 treatment included M1 to M2 microglia phenotype switching, blocking leukocyte transmigration, decreasing apoptotic and inflammatory factors, and promoting cellular viability.


Assuntos
Angiopoietina-1/farmacologia , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Integrina alfa5beta1/metabolismo , Integrina alfaVbeta3/metabolismo , Pulmão/irrigação sanguínea , Camundongos , Microglia/efeitos dos fármacos , Microvasos/patologia , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor TIE-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1
9.
Int J Nanomedicine ; 15: 3217-3233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440120

RESUMO

Introduction: Since CdTe quantum dots (QDs) are still widely considered as advanced fluorescent probes because of their far superior optical performance and fluorescence efficiency over non-cadmium QDs, it is important to find ways to control their toxicity. Methods: In this study, the adverse effects of two cadmium-containing QDs, ie, CdTe QDs and CdTe@ZnS QDs, on the nervous system of nematode C. elegans, the hippocampus of mice, and cultured microglia were measured in order to evaluate the neuroinflammation caused by cadmium-containing QDs and the potential mechanisms. Results: Firstly, we observed that cadmium-containing QD exposure-induced immune responses and neurobehavioral deficit in nematode C. elegans. In the mice treated with QDs, neuroinflammatory responses to QDs in the hippocampus, including microglial activation and IL-1ß release, occurred as well. When investigating the mechanisms of cadmium-containing QDs causing IL-1ß-mediated inflammation, the findings suggested that cadmium-containing QDs activated the NLRP3 inflammasome by causing excessive ROS generation, and resulted in IL-1ß release. Discussion: Even though the milder immune responses and neurotoxicity of CdTe@ZnS QDs compared with CdTe QDs indicated the protective role of ZnS coating, the inhibitions of NLRP3 expression and ROS production completely reduced the IL-1ß-mediated inflammation. This provided valuable information that inhibiting target molecules is an effective and efficient way to alleviate  the toxicity of cadmium-containing QDs, so it is important to evaluate QDs through a mechanism-based risk assessment.


Assuntos
Encéfalo/patologia , Compostos de Cádmio/farmacologia , Inflamação/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pontos Quânticos/química , Sulfetos/farmacologia , Telúrio/farmacologia , Compostos de Zinco/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/imunologia , Linhagem Celular , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos ICR , Microglia/efeitos dos fármacos , Microglia/patologia , Espécies Reativas de Oxigênio/metabolismo
10.
Nat Commun ; 11(1): 2358, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398649

RESUMO

Sphingosine kinase1 (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase2 (COX2) in neurons in a model of Alzheimer's disease (AD). However, the mechanism underlying this activity was unexplored. Here we show that N-acetyl sphingosine (N-AS) is first generated by acetyl-CoA and sphingosine through SphK1. N-AS then acetylates serine 565 (S565) of COX2, and the N-AS-acetylated COX2 induces the production of specialized pro-resolving mediators (SPMs). In a mouse model of AD, microglia show a reduction in N-AS generation, leading to decreased acetyl-S565 COX2 and SPM production. Treatment with N-AS increases acetylated COX2 and N-AS-triggered SPMs in microglia of AD mice, leading to resolution of neuroinflammation, an increase in microglial phagocytosis, and improved memory. Taken together, these results identify a role of N-AS in the dysfunction of microglia in AD.


Assuntos
Doença de Alzheimer/imunologia , Anti-Inflamatórios/farmacologia , Encéfalo/imunologia , Microglia/imunologia , Esfingosina/análogos & derivados , Acetilcoenzima A/metabolismo , Acetilação , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Encéfalo/patologia , Linhagem Celular , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Mutagênese , Neurônios , Fagocitose/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Presenilina-1/genética , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Serina/metabolismo , Esfingosina/metabolismo
11.
Nat Commun ; 11(1): 2360, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398677

RESUMO

Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [11C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals-with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.


Assuntos
Encéfalo/imunologia , Microglia/imunologia , Transtornos de Estresse Pós-Traumáticos/imunologia , Acetamidas/administração & dosagem , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Masculino , Microglia/patologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Piridinas/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Receptores de GABA/imunologia , Receptores de GABA/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Fatores Sexuais , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/patologia , Adulto Jovem
12.
Adv Exp Med Biol ; 1194: 303-314, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468546

RESUMO

MOTIVATION: In the last years, systems-level network-based approaches have gained ground in the research field of systems biology. These approaches are based on the analysis of high-throughput sequencing studies, which are rapidly increasing year by year. Nowadays, the single-cell RNA-sequencing, an optimized next-generation sequencing (NGS) technology that offers a better understanding of the function of an individual cell in the context of its microenvironment, prevails. RESULTS: Toward this direction, a method is developed in which active molecular subpathways are recorded during the time evolution of the disease under study. This method operates for expression profiling by high-throughput sequencing data. Its capability is based on capturing the temporal changes of local gene communities that form a disease-perturbed subpathway. The aforementioned methods are applied to real data from a recent study that uses single-cell RNA-sequencing data related with the progression of neurodegeneration. More specific, microglia cells were isolated from the hippocampus of a mouse model with Alzheimer's disease-like phenotypes and severe neurodegeneration and of control mice at multiple time points during progression of neurodegeneration. Our analysis offers a different view for neurodegeneration progression under the perspective of systems biology. CONCLUSION: Our approach into the molecular perspective using a temporal tracking of active pathways in neurodegeneration at single-cell resolution may offer new insights for designing new efficient strategies to treat Alzheimer's and other neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Biologia de Sistemas , Doença de Alzheimer/fisiopatologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Camundongos , Microglia/patologia , Análise de Sequência de RNA , Análise de Célula Única/normas , Biologia de Sistemas/métodos
13.
Arch Biochem Biophys ; 689: 108411, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450066

RESUMO

The process of ischemia/reperfusion (IR) in ischemic stroke often leads to significant cell death and permanent neuronal damage. Safe and effective treatments are urgently needed to mitigate the damage caused by IR injury. The naturally occurring pleiotropic peptide phoenixin 14 (PNX-14) has recently come to light as a potential treatment for IR injury. In the present study, we examined the effects of PNX-14 on several key processes involved in ischemic injury, such as pro-inflammatory cytokine expression, oxidative stress, and the related cascade mediated through the toll-like receptor 4 (TLR4) pathway, using BV2 microglia exposed to oxygen-glucose deprivation and reoxygenation (OGD/R). Our results demonstrate an acute ability of PNX-14 to regulate the expression levels of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). PNX-14 also prevented oxidative stress by reducing the generation of reactive oxygen species (ROS) and increasing the level of the antioxidant glutathione (GSH). Importantly, PNX-14 inhibited high-mobility group box 1 (HMGB1)/TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway, by inhibiting the activation of TLR4 and preventing the nuclear translocation of p65 protein. We further confirmed the cerebroprotective effects of PNX-14 in an MCAO rat model, which resulted in reduced infarct volume and decreased microglia activation. Together, the results of this study implicate a possible protective role of PNX-14 against various aspects of IR injury in vitro.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Hormônios Hipotalâmicos/uso terapêutico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Hormônios Peptídicos/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/patologia , Linhagem Celular , Masculino , Microglia/patologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
14.
DNA Cell Biol ; 39(6): 1064-1071, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32255663

RESUMO

Neuroinflammation is a critical mechanism responsible for the progression of Alzheimer's disease (AD). Recent studies reveal that Hippo/Yes-associated protein (YAP) signaling pathway is highly associated with a series of inflammation-related disorders. Glial cell line-derived neurotrophic factor (GDNF), with its neurotrophic and anti-apoptotic functions for nervous system, has been demonstrated to decrease the expression of proinflammatory mediators. Here we investigated whether Hippo/YAP signaling may affect amyloid-ß (Aß)-induced proinflammatory cytokine production in microglial cells and explored its relationship with the anti-inflammation function of GDNF. The results showed that Aß induced a decrease in the expression of YAP in microglia cells. YAP agonist XMU-MP-1 or its overexpression in microglial cells caused decreased expression of proinflammatory cytokines, whereas YAP antagonist Verteporfin or knockdown of YAP had the opposite effect. Treatment with GDNF resulted in upregulation of YAP expression and reduced the production of proinflammatory cytokines. Meanwhile YAP knockdown weakened the function of GDNF in microglial cells. In conclusion, Hippo/YAP pathway plays a critical role in effect of GDNF against Aß-induced inflammatory response in microglia. Targeting GDNF or Hippo/YAP signaling may be promising therapeutic approach for the treatment of AD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Peptídeos beta-Amiloides/farmacologia , Proteínas de Ciclo Celular/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Microglia/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Linhagem Celular , Citocinas/biossíntese , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Interferência de RNA
15.
PLoS One ; 15(4): e0226050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240164

RESUMO

Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80+ CD11b+ cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.


Assuntos
Encefalomielite Autoimune Experimental/genética , Lisofosfolipídeos/genética , Esclerose Múltipla/genética , Diester Fosfórico Hidrolases/genética , Animais , Antígeno CD11b/genética , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/fisiopatologia , Deleção de Genes , Expressão Gênica/genética , Humanos , Lisofosfolipídeos/biossíntese , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Esclerose Múltipla/sangue , Esclerose Múltipla/fisiopatologia , Transdução de Sinais/genética , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
16.
Stroke ; 51(5): 1587-1595, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312218

RESUMO

Background and Purpose- Women have worse stroke outcomes than men, especially after menopause. Few studies have focused on female-specific mechanisms, other than hormones. We investigated the role of the blood protein VTN (vitronectin) after ischemic stroke in mice. Methods- Adult male and female VTN knockout and wild-type littermates and C57BL/6 mice received a middle cerebral artery occlusion and the injured brain tissue analyzed 24 hours to 3 weeks later for cell loss and inflammation, as well as neurological function. Blood VTN levels were measured before and after stroke. Results- Intravenously injected VTN leaked extensively from bloodstream into brain infarct and penumbra by 24 hours after stroke. Strikingly, VTN was detrimental in female, but not male, mice, as shown by reduced brain injury (26.2±2.6% versus 13.4±3.8%; P=0.018; n=6 and 5) and forelimb dysfunction in female VTN knockout mice. Stroke increased plasma VTN 2- to 8-fold at 24 hours in females (36±4 versus 145±24 µg/mL; P<0.0001; n=10 and 7), but not males (62±8 versus 68±6; P>0.99; n=10 and 7), and returned to control levels by 7 days. Individually variable VTN levels at 24 hours correlated with stroke-induced brain injury at 7 days only in females. VTN promoted stroke-induced microglia/macrophage activation and leukocyte infiltration in females. Proinflammatory IL (interleukin)-6 greatly increased in the striatum at 24 hours in wild-type mice but was increased ≈60% less in female (739±159 versus 268±111; P=0.02; n=7 and 6), but not male (889±178 versus 1179±295; P=0.73; n=10 and 11), knockout mice. In individual wild-type females, plasma VTN levels correlated with striatal IL-6 expression at 24 hours. The female-specific effect of VTN-induced IL-6 expression following stroke was not due to gonadal hormones, as shown by ovariectomy and castration. Lastly, intrastriatal injection of IL-6 in female mice immediately before stroke reversed the VTN knockout phenotypes of reduced brain injury and microglia/macrophage activation. Conclusions- VTN plays a novel sexually dimorphic detrimental pathophysiological role in females and might ultimately be a therapeutic target to improve stroke outcomes in women.


Assuntos
Barreira Hematoencefálica/metabolismo , Infarto da Artéria Cerebral Média/genética , Inflamação/genética , Interleucina-6/genética , Vitronectina/genética , Animais , Fator Neurotrófico Ciliar/genética , Fator Neurotrófico Ciliar/metabolismo , Feminino , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação/metabolismo , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , RNA Mensageiro/metabolismo , Fatores Sexuais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Vitronectina/sangue , Vitronectina/metabolismo
17.
Nat Med ; 26(5): 769-780, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284590

RESUMO

Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.


Assuntos
Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Encéfalo/metabolismo , Líquido Cefalorraquidiano/metabolismo , Metabolismo Energético , Microglia/metabolismo , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Líquido Cefalorraquidiano/química , Estudos de Coortes , Progressão da Doença , Feminino , Redes Reguladoras de Genes/fisiologia , Humanos , Masculino , Espectrometria de Massas , Redes e Vias Metabólicas , Camundongos , Microglia/patologia , Microglia/fisiologia , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/líquido cefalorraquidiano , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologia , Proteômica/métodos , Tamanho da Amostra , Fatores de Tempo
18.
Cell ; 180(5): 833-846.e16, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142677

RESUMO

Cognitive dysfunction and reactive microglia are hallmarks of traumatic brain injury (TBI), yet whether these cells contribute to cognitive deficits and secondary inflammatory pathology remains poorly understood. Here, we show that removal of microglia from the mouse brain has little effect on the outcome of TBI, but inducing the turnover of these cells through either pharmacologic or genetic approaches can yield a neuroprotective microglial phenotype that profoundly aids recovery. The beneficial effects of these repopulating microglia are critically dependent on interleukin-6 (IL-6) trans-signaling via the soluble IL-6 receptor (IL-6R) and robustly support adult neurogenesis, specifically by augmenting the survival of newborn neurons that directly support cognitive function. We conclude that microglia in the mammalian brain can be manipulated to adopt a neuroprotective and pro-regenerative phenotype that can aid repair and alleviate the cognitive deficits arising from brain injury.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Interleucina-6/genética , Receptores de Interleucina-6/genética , Regeneração/genética , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Disfunção Cognitiva/terapia , Modelos Animais de Doenças , Humanos , Inflamação/genética , Inflamação/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/genética
19.
Acta Diabetol ; 57(7): 861-866, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32114640

RESUMO

AIMS: Hyperreflective foci (HF), detected in the retina of diabetic patients, suggest the presence of microglial activation and migration, while controversies still remain for the origin of HF to be precursors of hard exudates. We investigated the presence of HF and their association with dyslipidemia in serous retinal detachment (SRD)-type diabetic macular edema (DME). METHODS: Forty-two eyes in 42 patients with diabetic retinopathy (DR) and 22 eyes in 22 patients with branch retinal vascular occlusion (BRVO) showing macular edema were included in this study. The medical records and OCT findings were retrospectively reviewed in patients with SRD-type DME and compared with those with BRVO. The mean number of HF, the mean choroidal thickness, and lipid profiles were analyzed and compared between groups. RESULTS: The mean number of HF was significantly higher in DR group compared to BRVO group. Significant correlation of HF was noted with triglycerides (r = 0.523, P = 0.002). Triglycerides were significantly associated with HF by linear regression (ß = 0.012, 95% CI 0.001-0.024, P = 0.034) and remained significantly associated by multiple linear regression (ß = 0.014, 95% CI 0.003-0.025, P = 0.014). CONCLUSIONS: HF on OCT of DME patients could be indicative of activated microglia. HF are associated with dyslipidemia, especially high triglycerides, suggesting inflammatory reaction from dyslipidemia in diabetic retina.


Assuntos
Retinopatia Diabética/complicações , Dislipidemias/complicações , Edema Macular/complicações , Microglia/patologia , Retina/patologia , Descolamento Retiniano/complicações , Adulto , Idoso , Movimento Celular , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/patologia , Dislipidemias/diagnóstico , Dislipidemias/patologia , Feminino , Humanos , Edema Macular/diagnóstico , Edema Macular/patologia , Masculino , Microglia/fisiologia , Pessoa de Meia-Idade , Retina/diagnóstico por imagem , Retina/fisiopatologia , Oclusão da Artéria Retiniana/complicações , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/patologia , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual
20.
Toxicology ; 436: 152437, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169474

RESUMO

Mild cognitive impairment in Parkinson's disease (PD-MCI) is considered as a nonmotor clinical symptom in Parkinson's disease (PD). Microglia-mediated inflammation contributes to cognitive function impairment. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurons degeneration in PD. But whether P188 could ameliorate cognitive impairment in PD is still illusive. In the present study, we showed in a mouse model that paraquat (10 mg/kg) and maneb (30 mg/kg) (P + M) treatment intraperitoneally twice a week for 6 consecutive weeks resulted in cognitive deficits and synapse loss in hippocampus, together with DA neuron damage in the substantia nigra pars compacta (SNpc). P188 (0.8 g/kg) injection via tail vein 30 min after P + M administration significantly restored DA neuron numbers in SNpc and synapse density in hippocampus, and alleviated P + M-mediated cognitive function impairment in novel object recognition task and morris water maze task (MWM). Pathological synapse loss might be attributed to increased microglial phagocytic activity and cell density, and P188 prevented P + M-induced phagocytic state changes of microglia, such as increase in cell body size and decrease in process length, and upregulated microglia abundance in hippocampus. Consistently, P188 attenuated P + M-mediated increased mRNA levels of microglia proliferation related CSF1r and CSF2ra, microglial engulfment associated CD68, ICAM1, and ICAM2, and pro-inflammatory IL-6, IL-1ß, CD11b, and TNF-α in hippocampus. Together, these findings suggest that the biocompatible polymer P188 blunts microglia activation which may promote synaptic loss and exacerbate cognitive function in a mouse model of PD-MCI.


Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Parte Compacta da Substância Negra/efeitos dos fármacos , Poloxâmero/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Maneb , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Degeneração Neural , Paraquat , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/psicologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Fagocitose/efeitos dos fármacos , Poloxâmero/farmacocinética , Reconhecimento Psicológico/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia
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