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1.
Nat Rev Neurosci ; 21(2): 93-102, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31913356

RESUMO

A rapidly ageing population and a limited therapeutic toolbox urgently necessitate new approaches to treat neurodegenerative diseases. Brain ageing, the key risk factor for neurodegeneration, involves complex cellular and molecular processes that eventually result in cognitive decline. Although cell-intrinsic defects in neurons and glia may partially explain this decline, cell-extrinsic changes in the systemic environment, mediated by blood, have recently been shown to contribute to brain dysfunction with age. Here, we review the current understanding of how systemic factors mediate brain ageing, how these factors are regulated and how we can translate these findings into therapies for neurodegenerative diseases.


Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Homeostase , Doenças Neurodegenerativas/fisiopatologia , Envelhecimento/imunologia , Animais , Encéfalo/imunologia , Células Endoteliais/imunologia , Células Endoteliais/fisiologia , Exercício Físico/fisiologia , Humanos , Microbiota/imunologia , Microbiota/fisiologia , Doenças Neurodegenerativas/imunologia , Neuroglia/imunologia , Neuroglia/fisiologia , Neurônios/imunologia , Neurônios/fisiologia
2.
J Agric Food Chem ; 68(7): 1790-1807, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31241945

RESUMO

Age-associated pathophysiological changes such as neurodegenerative diseases are multifactorial conditions with increasing incidence and no existing cure. The possibility of altering the progression and development of these multifactorial diseases through diet is an attractive approach with increasing supporting data. Epidemiological and clinical studies have highlighted the health potential of diets rich in fruits and vegetables. Such food sources are rich in (poly)phenols, natural compounds increasingly associated with health benefits, having the potential to prevent or retard the development of various diseases. However, absorption and the blood concentration of (poly)phenols is very low when compared with their corresponding (poly)phenolic metabolites. Therefore, these serum-bioavailable metabolites are much more promising candidates to overcome cellular barriers and reach target tissues, such as the brain. Bearing this in mind, it will be reviewed that the molecular mechanisms underlying (poly)phenolic metabolites effects, range from 0.1 to <50 µM and their role on neuroinflammation, a central hallmark in neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas/dietoterapia , Doenças Neurodegenerativas/imunologia , Extratos Vegetais/metabolismo , Polifenóis/metabolismo , Animais , Frutas/química , Frutas/metabolismo , Humanos , Peso Molecular , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Extratos Vegetais/química , Polifenóis/química , Verduras/química , Verduras/metabolismo
3.
BMB Rep ; 53(1): 1-2, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31865963

RESUMO

Mitochondria is essential to generate metabolic energy in eukaryotic cells as well as to regulate calcium buffering, cell signaling, the production of reactive oxygen species (ROS), and apoptosis. They mainly produce most of the cellular energy derived from the breakdown of carbohydrates and fatty acids, which is consequently converted to ATP via oxidative phosphorylation. Mitochondria are also distinctive among the cytoplasmic organelles in that they contain their own DNA, which encodes limited number of mitochondrial proteins, tRNAs, and rRNAs. Evidence has accumulated from many reports, indicating that mitochondrial abnormalities are involved in age-related neurodegenerative diseases (NDDs). Causal factors for most age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis are largely unknown. Although genetic defects are reported to cause a small number of NDDs, cellular, molecular, and pathological mechanisms of disease progression and selective neuronal cell death are not understood fully in these diseases. Especially, age-dependent and mitochondriagenerated ROS has been identified as an important factor that is responsible for disease progression and cell death, particularly in late-onset diseases. Based on the current hypothesis supported by many recent findings, this issue discusses the roles of mitochondria in the progression of age-related neurodegenerative diseases, the connection between mitochondrial abnormalities and NDD, and the drug development targeted to mitochondria in NDDs. [BMB Reports 2020; 53(1): 1-2].


Assuntos
Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Apoptose , Autofagia/genética , Humanos , Inflamação/imunologia , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de GABA/imunologia , Receptores de GABA/metabolismo , Proteína Sequestossoma-1/metabolismo , Esfingolipídeos/imunologia , Esfingolipídeos/metabolismo
4.
Folia Neuropathol ; 57(3): 211-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588707

RESUMO

Through the use of RNA sequencing, microRNA (miRNA) and messenger RNA (mRNA) microfluidic array analysis, LED Northern, Western and ELISA analysis and multiple bioinformatics algorithms we have discovered a novel route for pathogenic communication between the human gastrointestinal (GI)-tract microbiome and the brain. The evidence suggests that this pathogenic gut-brain circuit involves: (i) lipopolysaccharide (LPS) from the GI-tract resident enterotoxigenic Gram-negative bacteria Bacteroides fragilis (BF-LPS); (ii) LPS transit across the GI-tract barrier into the systemic circulation; (iii) transport of a highly pro-inflammatory systemic BF-LPS across the blood-brain barrier (BBB) into the brain-parenchyma and neuronal-cytoplasm; (iv) activation and signaling via the pro-inflammatory NF-kB (p50/p65) transcription-factor complex; (v) NF-kB-coupling and significant up-regulation of the inducible pro-inflammatory microRNA-146a (miRNA-146a) and microRNA-155 (miRNA-155); each containing multiple NF-kB DNA-binding and activation sites in their immediate promoters; and (vi) subsequent down-regulation of miRNA-146a-miRNA-155 regulated mRNA targets such as that encoding complement factor H (CFH), a soluble complement control glycoprotein and key repressor of the innate-immune response. Down-regulated CFH expression activates the complement-system, the major non-cellular component of the innate-immune system while propagating neuro-inflammation. Other GI-tract microbes and their highly complex pro-inflammatory exudates may contribute to this pathogenic GI-tract-brain pathway. We speculate that it may be significant that the first Gram-negative anaerobic bacterial species intensively studied as a potential contributor to the onset of Alzheimer's disease (AD), that being the bacillus Bacteroides fragilis appears to utilize damaged or leaky physiological barriers and an activated NF-kB (p50-p65) - pro-inflammatory miRNA-146a-miRNA-155 signaling circuit to convey microbiome-derived pathogenic signals into the brain.


Assuntos
Encéfalo/imunologia , Microbioma Gastrointestinal/imunologia , Doenças Neurodegenerativas/imunologia , Neuroimunomodulação/fisiologia , Encéfalo/fisiopatologia , Humanos , Lipopolissacarídeos/imunologia , MicroRNAs/imunologia , NF-kappa B/imunologia , Doenças Neurodegenerativas/fisiopatologia
5.
Neurología (Barc., Ed. impr.) ; 34(8): 503-509, oct. 2019. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-186353

RESUMO

Introducción: La exposición a dosis bajas de O3 conduce a un estado de estrés oxidativo. Algunos estudios muestran que el estado de estrés oxidativo puede modular tanto el SNC como la inflamación sistémica, que son importantes para el desarrollo de la enfermedad de Alzheimer. Objetivo: Evaluar la frecuencia de células tipo Th17, la concentración de IL-17A en plasma y la inmunorreactividad del hipocampo a IL-17A en ratas expuestas a dosis bajas de O3.Métodos: Ciento ocho ratas Wistar machos fueron divididas en 6 grupos (n = 18) con los siguientes tratamientos: control (sin O3) y O3 (0,25 ppm, diario por 4h) durante 7, 15, 30, 60 y 90 días. De cada grupo se decapitaron 12 animales, se tomó una muestra de sangre periférica para aislar el plasma y las células mononucleares. La IL-17A plasmática se evaluó mediante LUMINEX y la frecuencia de células de tipo Th17 por citometría de flujo. Las ratas restantes se anestesiaron y se perfundieron para inmunohistoquímica en el hipocampo. Resultados: Muestran que la exposición durante 7 días a O3 produce un aumento significativo en la frecuencia de células tipo Th17 y los niveles de IL-17A en sangre periférica. Sin embargo, existe una disminución de Th17/IL-17A en la periferia desde el día 15. También se encontró un aumento de IL-17A en el hipocampo desde los 30 días de exposición. Conclusión: El O3 produce un efecto sistémico a corto plazo de tipo Th17/IL-17A y un aumento de IL-17A en el tejido del hipocampo durante el proceso neurodegenerativo crónico


Introduction: Exposure to low doses of O3 leads to a state of oxidative stress. Some studies show that oxidative stress can modulate both the CNS and systemic inflammation, which are important factors in the development of Alzheimer disease (AD).Objective: This study aims to evaluate changes in the frequency of Th17-like cells (CD3+CD4+IL-17A+), the concentration of IL-17A in peripheral blood, and hippocampal immunoreactivity to IL-17A in rats exposed to low doses of O3. Methods: One hundred eight male Wistar rats were randomly assigned to 6 groups (n = 18) receiving the following treatments: control (O3 free) or O3 exposure (0.25 ppm, 4hours daily) over 7, 15, 30, 60, and 90 days. Twelve animals from each group were decapitated and a peripheral blood sample was taken to isolate plasma and mononuclear cells. Plasma IL-17A was quantified using LUMINEX, while Th17-like cells were counted using flow cytometry. The remaining 6 rats were deeply anaesthetised and underwent transcardial perfusion for immunohistological study of the hippocampus. Results: Results show that exposure to O3 over 7 days resulted in a significant increase in the frequency of Th17-like cells and levels of IL-17A in peripheral blood. However, levels of Th17/IL-17A in peripheral blood were lower at day 15 of exposure. We also observed increased IL-17A in the hippocampus beginning at 30 days of exposure. Conclusion: These results indicate that O3 induces a short-term, systemic Th17-like/IL-17A effect and an increase of IL-17A in the hippocampal tissue during the chronic neurodegenerative process


Assuntos
Animais , Masculino , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Interleucina-17/sangue , Doenças Neurodegenerativas/imunologia , Ozônio/administração & dosagem , Células Th17/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar
6.
Adv Exp Med Biol ; 1161: 133-148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562628

RESUMO

Bioactive lipids, or lipid mediators, are utilized for intercellular communications. They are rapidly produced in response to various stimuli and exported to extracellular spaces followed by binding to cell surface G protein-coupled receptors (GPCRs) or nuclear receptors. Many drugs targeting lipid signaling such as non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandins, and antagonists for lipid GPCRs are in use. For example, the sphingolipid analog, fingolimod (also known as FTY720), was the first oral disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (MS), whose mechanisms of action (MOA) includes sequestration of pathogenic lymphocytes into secondary lymphoid organs, as well as astrocytic modulation, via down-regulation of the sphingosine 1-phosphate (S1P) receptor, S1P1, by in vivo-phosphorylated fingolimod. Though the cause of MS is still under debate, MS is considered to be an autoimmune demyelinating and neurodegenerative disease. This review summarizes the involvement of bioactive lipids (prostaglandins, leukotrienes, platelet-activating factors, lysophosphatidic acid, and S1P) in MS and the animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation, along with pharmacological inhibition, of lipid metabolic enzymes and lipid GPCRs revealed that each bioactive lipid has a unique role in regulating immune and neural functions, including helper T cell (TH1 and TH17) differentiation and proliferation, immune cell migration, astrocyte responses, endothelium function, and microglial phagocytosis. A systematic understanding of bioactive lipids in MS and EAE dredges up information about understudied lipid signaling pathways, which should be clarified in the near future to better understand MS pathology and to develop novel DMTs.


Assuntos
Encefalomielite Autoimune Experimental , Metabolismo dos Lipídeos , Lipídeos , Esclerose Múltipla , Doenças Neurodegenerativas , Animais , Modelos Animais de Doenças , Lipídeos/química , Esclerose Múltipla/fisiopatologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/fisiopatologia
7.
J Biochem ; 166(3): 213-221, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251338

RESUMO

Central nervous system (CNS)-related disorders, including neurodegenerative diseases, are common but difficult to treat. As effective medical interventions are limited, those diseases will likely continue adversely affecting people's health. There is evidence that the hyperactivation of innate immunity is a hallmark of most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and polyglutamine diseases. In mammalian and fly CNS, the presence of noninfectious ligands, including danger-associated molecular patterns, is recognized by (micro)glial cells, inducing the expression of proinflammatory cytokines. Such inflammation may contribute to the onset and progression of neurodegenerative states. Studies using fruit flies have shed light on the types of signals, receptors and cells responsible for inducing the inflammation that leads to neurodegeneration. Researchers are using fly models to assess the mechanisms of sterile inflammation in the brain and its link to progressive neurodegeneration. Given the similarity of its physiological system and biochemical function to those of mammals, especially in activating and regulating innate immune signalling, Drosophila can be a versatile model system for studying the mechanisms and biological significance of sterile inflammatory responses in the pathogenesis of neurodegenerative diseases. Such knowledge would greatly facilitate the quest for a novel effective treatment for neurodegenerative diseases.


Assuntos
Modelos Animais de Doenças , Drosophila , Inflamação/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Drosophila/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia
8.
Int J Mol Sci ; 20(10)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137759

RESUMO

The concept of „trained innate immunity" is understood as the ability of innate immune cells to remember invading agents and to respond nonspecifically to reinfection with increased strength. Trained immunity is orchestrated by epigenetic modifications leading to changes in gene expression and cell physiology. Although this phenomenon was originally seen mainly as a beneficial effect, since it confers broad immunological protection, enhanced immune response of reprogrammed innate immune cells might result in the development or persistence of chronic metabolic, autoimmune or neuroinfalmmatory disorders. This paper overviews several examples where the induction of trained immunity may be essential in the development of diseases characterized by flawed innate immune response.


Assuntos
Aterosclerose/imunologia , Diabetes Mellitus/imunologia , Imunidade Inata , Memória Imunológica , Doenças Neurodegenerativas/imunologia , Animais , Humanos
9.
Mediators Inflamm ; 2019: 4050796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31065234

RESUMO

Mitochondrial dysfunction has been established as a common feature of neurodegenerative disorders that contributes to disease pathology by causing impaired cellular energy production. Mitochondrial molecules released into the extracellular space following neuronal damage or death may also play a role in these diseases by acting as signaling molecules called damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs have been shown to initiate proinflammatory immune responses from nonneuronal glial cells, including microglia and astrocytes; thereby, they have the potential to contribute to the chronic neuroinflammation present in these disorders accelerating the degeneration of neurons. In this review, we highlight the mitochondrial DAMPs cytochrome c (CytC), mitochondrial transcription factor A (TFAM), and cardiolipin and explore their potential role in the central nervous system disorders including Alzheimer's disease and Parkinson's disease, which are characterized by neurodegeneration and chronic neuroinflammation.


Assuntos
Inflamação/imunologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Neurodegenerativas/imunologia , Animais , Citocromos c/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Inflamação/metabolismo , Proteínas Mitocondriais/metabolismo , Doenças Neurodegenerativas/metabolismo , Fatores de Transcrição/metabolismo
10.
Croat Med J ; 60(2): 127-140, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31044584

RESUMO

AIM: To propose potential mechanisms of action of electromagnetic fields (EMF) on astrocytes and microglia and to elucidate the role of heat shock proteins (HSP), adenosine triphosphate (ATP), calcium ions (Ca2+), and hypoxia-inducible factor 1α (HIF1α) in neurorestoration following the application of EMF. METHODS: We reviewed the existing studies within the public domain and cross-evaluated their results in order to conclude on the molecular mechanisms of microglia-astrocyte crosstalk at work during EMF treatment. RESULTS: The existing studies suggest that EMF induces the increase of HSP70 expression and inhibition of HIF1α, thus decreasing inflammation and allowing the microglia-astrocyte crosstalk to initiate the formation of a glial scar within the central nervous system. Furthermore, by potentially up-regulating A2A and A3 adenosine receptors, EMF increases cAMP accumulation from astrocytes and reduces the expression of inflammatory cytokines TNF α and IL-8, thus initiating neurorestoration. CONCLUSION: The microglia-astrocyte crosstalk during EMF treatment is crucial for the initiation of neurorestoration. Elucidating the exact mechanisms of EMF actions upon microglia and astrocytes, and its role in neurorestoration could be a key step in further research of the therapeutic potential of EMFs in various neurological disorders.


Assuntos
Astrócitos/fisiologia , Terapia de Campo Magnético , Microglia/fisiologia , Doenças Neurodegenerativas/terapia , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Citocinas , Campos Eletromagnéticos , Proteínas de Choque Térmico/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Inflamação/terapia , Doenças Neurodegenerativas/imunologia , Receptor Cross-Talk , Fator de Necrose Tumoral alfa
11.
Immunity ; 50(4): 778-795, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995499

RESUMO

Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine.


Assuntos
Imunidade Adaptativa/imunologia , Citocinas/fisiologia , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-1/fisiologia , Animais , Doenças Cardiovasculares/imunologia , Citocinas/genética , Citocinas/imunologia , Gastroenteropatias/imunologia , Hematopoese/imunologia , Humanos , Interleucina-1/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Doenças Neurodegenerativas/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia
12.
Immunity ; 50(4): 955-974, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995509

RESUMO

Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and emerging mechanisms for three key immune pathways implicated in disease, the growth factor TGF-ß, the complement cascade, and the extracellular receptor TREM2. These immune signaling pathways are important under both healthy and neurodegenerative conditions, and recent work has highlighted new functional aspects of their signaling. Finally, we assess future directions for immune-related research in neurodegeneration and potential avenues for immune-related therapies.


Assuntos
Doenças Neurodegenerativas/imunologia , Transdução de Sinais/imunologia , Envelhecimento/imunologia , Animais , Ativação do Complemento , Progressão da Doença , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gliose/imunologia , Gliose/patologia , Humanos , Imunidade Inata , Inflamação/imunologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/imunologia , Modelos Imunológicos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/terapia , Agregação Patológica de Proteínas/imunologia , Receptores Imunológicos/imunologia , Fator de Crescimento Transformador beta/imunologia
13.
Neuron ; 101(6): 1003-1015, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897353

RESUMO

Immunoproteostasis is a term used to reflect interactions between the immune system and the proteinopathies that are presumptive "triggers" of many neurodegenerative disorders. The study of immunoproteostasis is bolstered by several observations. Mutations or rare variants in genes expressed in microglial cells, known to regulate immune functions, or both can cause, or alter risk for, various neurodegenerative disorders. Additionally, genetic association studies identify numerous loci harboring genes that encode proteins of known immune function that alter risk of developing Alzheimer's disease (AD) and other neurodegenerative proteinopathies. Further, preclinical studies reveal beneficial effects and liabilities of manipulating immune pathways in various neurodegenerative disease models. Although there are concerns that manipulation of the immune system may cause more harm than good, there is considerable interest in developing immune modulatory therapies for neurodegenerative disorders. Herein, I highlight the promise and challenges of harnessing immunoproteostasis to treat neurodegenerative proteinopathies.


Assuntos
Doença de Alzheimer/imunologia , Imunoproteínas/imunologia , Inflamação/imunologia , Microglia/imunologia , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Predisposição Genética para Doença , Humanos , Imunoproteínas/genética , Camundongos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/terapia , Proteostase
14.
Subcell Biochem ; 91: 21-43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30888648

RESUMO

Aging leads to numerous changes that affect all physiological systems of the body including the immune system, causing greater susceptibility to infectious disease and contributing to the cardiovascular, metabolic, autoimmune, and neurodegenerative diseases of aging. The immune system is itself also influenced by age-associated changes occurring in such physiological systems as the endocrine, nervous, digestive, cardio-vascular and muscle-skeletal systems. This chapter describes the multidimensional effects of aging on the most important components of the immune system. It considers the age-related changes in immune cells and molecules of innate and adaptive immunity and consequent impairments in their ability to communicate with each other and with their aged environment. The contribution of age-related dysregulation of hematopoiesis, required for continuous replenishment of immune cells throughout life, is discussed in this context, as is the developmentally-programmed phenomenon of thymic involution that limits the output of naïve T cells and markedly contributes to differences between younger and older people in the distribution of peripheral blood T-cell types. How all these changes may contribute to low-grade inflammation, sometimes dubbed "inflammaging", is considered. Due to findings implicating elevated inflammatory immuno-mediators in age-associated chronic autoimmune and neurodegenerative processes, evidence for their possible contribution to neuroinflammation is reviewed.


Assuntos
Envelhecimento/imunologia , Envelhecimento/patologia , Sistema Imunitário/patologia , Humanos , Sistema Imunitário/imunologia , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia
15.
J Neuroinflammation ; 16(1): 53, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823925

RESUMO

Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.


Assuntos
Encéfalo/fisiologia , Doenças do Sistema Nervoso Central/imunologia , Microbioma Gastrointestinal/imunologia , Fenômenos do Sistema Imunológico/fisiologia , Animais , Doenças do Sistema Nervoso Central/fisiopatologia , Humanos , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/fisiopatologia
17.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717168

RESUMO

Long non-coding RNAs (lncRNAs) are involved in a variety of biological and cellular processes as well as in physiologic and pathophysiologic events. This review summarizes recent literature about the role of the lncRNA nuclear enriched abundant transcript 1 (NEAT1) in non-cancerous diseases with a special focus on viral infections and neurodegenerative diseases. In contrast to its role as competing endogenous RNA (ceRNA) in carcinogenesis, NEAT1's function in non-cancerous diseases predominantly focuses on paraspeckle-mediated effects on gene expression. This involves processes such as nuclear retention of mRNAs or sequestration of paraspeckle proteins from specific promoters, resulting in transcriptional induction or repression of genes involved in regulating the immune system or neurodegenerative processes. NEAT1 expression is aberrantly-mostly upregulated-in non-cancerous pathological conditions, indicating that it could serve as potential prognostic biomarker. Additional studies are needed to elucidate NEAT1's capability to be a therapeutic target for non-cancerous diseases.


Assuntos
Doenças Neurodegenerativas/genética , Proteínas Nucleares/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Viroses/genética , Biomarcadores/metabolismo , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Família Multigênica , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Proteínas Nucleares/imunologia , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , RNA Longo não Codificante/imunologia , Proteínas de Ligação a RNA/imunologia , Transdução de Sinais , Viroses/diagnóstico , Viroses/imunologia , Viroses/virologia
18.
Nature ; 566(7745): 503-508, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30787438

RESUMO

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein ß-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of ß-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, ß-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of ß-synuclein in provoking T-cell-mediated pathology of the central nervous system.


Assuntos
Substância Cinzenta/imunologia , Substância Cinzenta/patologia , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Crônica Progressiva/patologia , Linfócitos T/imunologia , beta-Sinucleína/imunologia , Animais , Encéfalo/patologia , Movimento Celular/imunologia , Feminino , Regulação da Expressão Gênica , Gliose/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Esclerose Múltipla Crônica Progressiva/sangue , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Ratos , Ratos Endogâmicos Lew , Linfócitos T/metabolismo , Linfócitos T/patologia , beta-Sinucleína/análise , beta-Sinucleína/genética , beta-Sinucleína/metabolismo
19.
Viruses ; 11(1)2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650564

RESUMO

Prion disorders are transmissible diseases caused by a proteinaceous infectious agent that can infect the lymphatic and nervous systems. The clinical features of prion diseases can vary, but common hallmarks in the central nervous system (CNS) are deposition of abnormally folded protease-resistant prion protein (PrPres or PrPSc), astrogliosis, microgliosis, and neurodegeneration. Numerous proinflammatory effectors expressed by astrocytes and microglia are increased in the brain during prion infection, with many of them potentially damaging to neurons when chronically upregulated. Microglia are important first responders to foreign agents and damaged cells in the CNS, but these immune-like cells also serve many essential functions in the healthy CNS. Our current understanding is that microglia are beneficial during prion infection and critical to host defense against prion disease. Studies indicate that reduction of the microglial population accelerates disease and increases PrPSc burden in the CNS. Thus, microglia are unlikely to be a foci of prion propagation in the brain. In contrast, neurons and astrocytes are known to be involved in prion replication and spread. Moreover, certain astrocytes, such as A1 reactive astrocytes, have proven neurotoxic in other neurodegenerative diseases, and thus might also influence the progression of prion-associated neurodegeneration.


Assuntos
Inflamação , Microglia/imunologia , Doenças Priônicas/patologia , Príons/imunologia , Animais , Astrócitos/imunologia , Astrócitos/patologia , Encéfalo/imunologia , Encéfalo/patologia , Humanos , Camundongos , Microglia/patologia , Doenças Neurodegenerativas/imunologia , Neurônios/imunologia , Neurônios/patologia , Proteínas PrPSc/imunologia , Proteínas PrPSc/patogenicidade , Doenças Priônicas/imunologia
20.
Acta Biomater ; 83: 13-28, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30414483

RESUMO

Microglia are multi-functional cells that play a vital role in establishing and maintaining the function of the nervous system and determining the fate of neurons following injury or neuropathology. The roles of microglia are diverse and essential to the capacity of the nervous system to recover from injury, however sustained inflammation can limit recovery and drive chronic disease processes such as neurodegenerative disorders. When assessing implantable therapeutic devices in the central nervous system, an improved lifetime of the implant is considered achievable through the attenuation of microglial inflammation. Consequently, there is a tremendous underexplored potential in biomaterial and engineered design to modulate neuroinflammation for therapeutic benefit. Several strategies for improving device compatibility reviewed here include: biocompatible coatings, improved designs in finer and flexible shapes to reduce tissue shear-related scarring, and loading of anti-inflammatory drugs. Studies about microglial cell cultures in 3D hydrogels and nanoscaffolds to assess various injuries and disorders are also discussed. A variety of other microglia-targeting treatments are also reviewed, including nanoparticulate systems, cellular backpacks, and gold plinths, with the intention of delivering anti-inflammatory drugs by targeting the phagocytic nature of microglia. Overall, this review highlights recent advances in biomaterials targeting microglia and inflammatory function with the potential for improving implant rejection and biocompatibility studies. STATEMENT OF SIGNIFICANCE: Microglia are the resident immune cells of the central nervous system, and thus play a central role in the neuroinflammatory response against conditions than span acute injuries, neuropsychiatric disorders, and neurodegenerative disorders. This review article presents a summary of biomaterials research that target microglia and other glial cells in order to attenuate neuroinflammation, including but not limited to: design of mechanically compliant and biocompatible stimulation electrodes, hydrogels for high-throughput 3D modelling of nervous tissue, and uptake of nanoparticle drug delivery systems. The goal of this paper is to identify strengths and gaps in the relevant literature, and to promote further consideration of microglia behaviour and neuroinflammation in biomaterial design.


Assuntos
Anti-Inflamatórios/uso terapêutico , Materiais Revestidos Biocompatíveis/uso terapêutico , Sistemas de Liberação de Medicamentos , Microglia/imunologia , Doenças Neurodegenerativas , Animais , Técnicas de Cultura de Células , Humanos , Hidrogéis/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Nanoestruturas/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia , Tecidos Suporte
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