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1.
J Pharmacol Sci ; 144(2): 76-82, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32736867

RESUMO

Astrocytes, comprising the primary glial-cell type, are involved in the formation and maturation of synapses, and thus contribute to sustainable synaptic transmission between neurons. Given that the animals in higher phylogenetic tree have brains with a higher density of glial cells with respect to neurons, there is a possibility that the relative astrocytic density directly influences synaptic transmission. However, the notion has not been tested thoroughly. Here we addressed it, by using a primary culture preparation where single hippocampal neurons are surrounded by a variable but a countable number of cortical astrocytes in dot-patterned microislands, and recording synaptic transmission by patch-clamp electrophysiology. Neurons with a higher astrocytic density showed a higher amplitude of the evoked excitatory postsynaptic current than that of neurons with a lower astrocytic density. The size of the readily releasable pool of synaptic vesicles per neuron was significantly larger. The frequency of spontaneous synaptic transmission was higher, but the amplitude was unchanged. The number of morphologically identified glutamatergic synapses was comparable, but the percentage of functional ones was increased, indicating a lower ratio of presynaptically silent synapses. Taken together, the higher astrocytic density enhanced excitatory synaptic transmission by increasing the fraction of functional synapses through presynaptic un-silencing.


Assuntos
Astrócitos/fisiologia , Encéfalo/citologia , Neurônios/fisiologia , Sinapses/fisiologia , Transmissão Sináptica , Animais , Astrócitos/patologia , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores , Feminino , Camundongos Endogâmicos ICR , Neurônios/patologia , Filogenia , Gravidez
3.
Life Sci ; 258: 118099, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682917

RESUMO

Although emerging evidence has highlighted the heterogeneities of astrocytes under physiological versus pathological conditions, little is known regarding these processes in different brain regions during stress. Thus, the present study established a mouse model of chronic social defeat stress (CSDS) and isolated astrocytes from the medial prefrontal cortex (mPFC) and hippocampus. The results revealed dramatic A1-specific (neurotoxic phenotype) astrocytic responses, depressive-like behaviors, and significant inhibition of neuronal activities in both the mPFC and hippocampus according to electrophysiological data. Subsequently, astrocytes in the mPFC and hippocampus of CSDS mice were suppressed and this reversed the astrocytic responses and rescued depressive-like behaviors. Furthermore, when astrocytes were activated in the mPFC and hippocampus in healthy mice, there was a non-specific phenotypic activation of astrocytes in the absence of depressive-like behaviors. Next, microglia were depleted and the mice subsequently performed in the CSDS model; this reduced astrocyte responses and restored depressive-like behaviors. On the other hand, when microglia were depleted but astrocytes were activated in CSDS mice, this abolished the restoration of microglia depletion-induced depressive-like behaviors. Taken together, these results indicate that neuronal inhibition by astrocytes in the mPFC and hippocampus contributed to depressive-like behaviors mediated by activated microglia. This study provides evidence regarding the interaction of microglia and astrocytes during stress and how that relationship can trigger depressive-like behaviors.


Assuntos
Astrócitos/patologia , Comportamento Animal , Depressão/psicologia , Neurônios/patologia , Estresse Psicológico/patologia , Animais , Doença Crônica , Hipocampo/patologia , Locomoção , Masculino , Camundongos , Inibição Neural , Neuroglia/metabolismo , Córtex Pré-Frontal/patologia
4.
PLoS Pathog ; 16(6): e1008381, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32525948

RESUMO

HIV invades the brain during acute infection. Yet, it is unknown whether long-lived infected brain cells release productive virus that can egress from the brain to re-seed peripheral organs. This understanding has significant implication for the brain as a reservoir for HIV and most importantly HIV interplay between the brain and peripheral organs. Given the sheer number of astrocytes in the human brain and their controversial role in HIV infection, we evaluated their infection in vivo and whether HIV infected astrocytes can support HIV egress to peripheral organs. We developed two novel models of chimeric human astrocyte/human peripheral blood mononuclear cells: NOD/scid-IL-2Rgc null (NSG) mice (huAstro/HuPBMCs) whereby we transplanted HIV (non-pseudotyped or VSVg-pseudotyped) infected or uninfected primary human fetal astrocytes (NHAs) or an astrocytoma cell line (U138MG) into the brain of neonate or adult NSG mice and reconstituted the animals with human peripheral blood mononuclear cells (PBMCs). We also transplanted uninfected astrocytes into the brain of NSG mice and reconstituted with infected PBMCs to mimic a biological infection course. As expected, the xenotransplanted astrocytes did not escape/migrate out of the brain and the blood brain barrier (BBB) was intact in this model. We demonstrate that astrocytes support HIV infection in vivo and egress to peripheral organs, at least in part, through trafficking of infected CD4+ T cells out of the brain. Astrocyte-derived HIV egress persists, albeit at low levels, under combination antiretroviral therapy (cART). Egressed HIV evolved with a pattern and rate typical of acute peripheral infection. Lastly, analysis of human cortical or hippocampal brain regions of donors under cART revealed that astrocytes harbor between 0.4-5.2% integrated HIV gag DNA and 2-7% are HIV gag mRNA positive. These studies establish a paradigm shift in the dynamic interaction between the brain and peripheral organs which can inform eradication of HIV reservoirs.


Assuntos
Astrócitos , Barreira Hematoencefálica , Infecções por HIV , HIV-1/metabolismo , Hipocampo , Liberação de Vírus , Animais , Antirretrovirais/farmacologia , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/virologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/virologia , Linhagem Celular Tumoral , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/patologia , HIV-1/genética , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/virologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID
5.
Nat Commun ; 11(1): 2484, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424276

RESUMO

DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5XFAD mouse model of Alzheimer's disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5XFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Dano ao DNA , DNA Glicosilases/metabolismo , Histona Desacetilase 1/metabolismo , Estresse Oxidativo , Acetilação , Envelhecimento/genética , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Sequência de Bases , Benzofenonas/farmacologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Ontologia Genética , Guanina/análogos & derivados , Guanina/metabolismo , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Regiões Promotoras Genéticas/genética
6.
PLoS One ; 15(5): e0232779, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365083

RESUMO

Apoptosis of neurovascular cells, including astroglial cells, contributes to the pathogenesis of diseases in which neurovascular disruption plays a central role. Bim is a pro-apoptotic protein that modulates not only apoptosis but also various cellular functions such as migration and extracellular matrix protein expression. Astroglial cells act as an intermediary between neural and vascular cells facilitating retinal vascular development and remodeling while maintaining normal vascular function and neuronal integrity. We previously showed that Bim deficient (Bim -/-) mice were protected from hyperoxia mediated vessel obliteration and ischemia-mediated retinal neovascularization. However, the underlying mechanisms and more specifically the role Bim expression in astroglial cells play remains elusive. Here, using retinal astroglial cells prepared from wild-type and Bim -/- mice, we determined the impact of Bim expression in retinal astroglial cell function. We showed that astroglial cells lacking Bim expression demonstrate increased VEGF expression and altered matricellular protein production including increased expression of thrombospondin-2 (TSP2), osteopontin and SPARC. Bim deficient astroglial cells also exhibited altered proliferation, migration, adhesion to various extracellular matrix proteins and increased expression of inflammatory mediators. Thus, our data emphasizes the importance of Bim expression in retinal astroglia cell autonomous regulatory mechanisms, which could influence neurovascular function.


Assuntos
Astrócitos/metabolismo , Proteína 11 Semelhante a Bcl-2/genética , Inflamação/genética , Retina/metabolismo , Animais , Apoptose/genética , Astrócitos/patologia , Movimento Celular/genética , Proliferação de Células/genética , Proteínas da Matriz Extracelular/genética , Regulação da Expressão Gênica/genética , Humanos , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Neovascularização Fisiológica/genética , Neurônios/metabolismo , Osteonectina/genética , Osteopontina/genética , Retina/patologia , Trombospondinas/genética , Fator A de Crescimento do Endotélio Vascular/genética
7.
PLoS One ; 15(4): e0229520, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32236105

RESUMO

Therapeutic hypothermia (TH) is an attractive target for mild traumatic brain injury (mTBI) treatment, yet significant gaps in our mechanistic understanding of TH, especially at the cellular level, remain and need to be addressed for significant forward progress to be made. Using a recently-established 3D in-vitro neural hydrogel model for mTBI we investigated the efficacy of TH after compressive impact injury and established critical treatment parameters including target cooling temperature, and time windows for application and maintenance of TH. Across four temperatures evaluated (31.5, 33, 35, and 37°C), 33°C was found to be most neuroprotective after 24 and 48 hours post-injury. Assessment of TH administration onset time and duration showed that TH should be administered within 4 hours post-injury and be maintained for at least 6 hours for achieving maximum viability. Cellular imaging showed TH reduced the percentage of cells positive for caspases 3/7 and increased the expression of calpastatin, an endogenous neuroprotectant. These findings provide significant new insight into the biological parameter space that renders TH effective in mitigating the deleterious effects of cellular mTBI and provides a quantitative foundation for the future development of animal and preclinical treatment protocols.


Assuntos
Astrócitos/metabolismo , Lesões Encefálicas Traumáticas/terapia , Encéfalo , Hipotermia Induzida/métodos , Neurônios/metabolismo , Células-Tronco/metabolismo , Animais , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Células Cultivadas , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Ratos Sprague-Dawley , Células-Tronco/patologia
8.
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
9.
Nat Neurosci ; 23(6): 701-706, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341542

RESUMO

The role of non-neuronal cells in Alzheimer's disease progression has not been fully elucidated. Using single-nucleus RNA sequencing, we identified a population of disease-associated astrocytes in an Alzheimer's disease mouse model. These disease-associated astrocytes appeared at early disease stages and increased in abundance with disease progression. We discovered that similar astrocytes appeared in aged wild-type mice and in aging human brains, suggesting their linkage to genetic and age-related factors.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Astrócitos/patologia , Encéfalo/patologia , Hipocampo/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos
10.
Clin Exp Metastasis ; 37(3): 401-412, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32279122

RESUMO

The brain is often reported as the first site of recurrence among breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Although most HER2+tumors metastasize to the subcortical region of the brain, a subset develops in the cortical region. We hypothesize that factors in cerebrospinal fluid (CSF) play a critical role in the adaptation, proliferation, and establishment of cortical metastases. We established novel cell lines using patient biopsies to model breast cancer cortical and subcortical metastases. We assessed the localization and growth of these cells in vivo and proliferation and apoptosis in vitro under various conditions. Proteomic analysis of human CSF identified astrocyte-derived factors that support the proliferation of cortical metastases, and we used neutralizing antibodies to test the effects of inhibiting these factors both in vivo and in vitro. The cortical breast cancer brain metastatic cells exhibited greater proliferation than subcortical breast cancer brain metastatic cells in CSF containing several growth factors that nourish both the CNS and tumor cells. Specifically, the astrocytic paracrine factors IGFBP2 and CHI3LI promoted the proliferation of cortical metastatic cells and the formation of metastatic lesions. Disruption of these factors suppressed astrocyte-tumor cell interactions in vitro and the growth of cortical tumors in vivo. Our findings suggest that inhibition of IGFBP2 and CHI3LI signaling, in addition to existing treatment modalities, may be an effective therapeutic strategy targeting breast cancer cortical metastasis.


Assuntos
Astrócitos/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Líquido Cefalorraquidiano/citologia , Proteína 1 Semelhante à Quitinase-3/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/líquido cefalorraquidiano , Proliferação de Células/efeitos dos fármacos , Córtex Cerebral/patologia , Proteína 1 Semelhante à Quitinase-3/antagonistas & inibidores , Técnicas de Cocultura , Feminino , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/antagonistas & inibidores , Camundongos , Comunicação Parácrina , Cultura Primária de Células , Proteômica , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Invest Ophthalmol Vis Sci ; 61(4): 1, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32271890

RESUMO

Purpose: Purpose The role of endothelial Yes-associated protein 1 (YAP) in the pathogenesis of retinal angiogenesis and the astrocyte network in the mouse oxygen-induced retinopathy (OIR) model is unknown. Methods: For in vivo studies, OIR was induced in conditional endothelial YAP knockout mice and their wild-type littermates. Retinal vascularization and the astrocyte network were evaluated by whole-mount fluorescence and Western blotting. In vitro experiments were performed in astrocytes cultured with human microvascular endothelial cell-1-conditioned medium to analyze the mechanisms underlying the effect of endothelial YAP on astrocytes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Astrócitos/patologia , Proteínas de Ciclo Celular/fisiologia , Células Endoteliais/metabolismo , Fator Inibidor de Leucemia/metabolismo , Neovascularização Retiniana/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Proliferação de Células , Células Cultivadas , Meios de Cultivo Condicionados , Citoplasma/metabolismo , Modelos Animais de Doenças , Técnica Indireta de Fluorescência para Anticorpo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Oxigênio/toxicidade , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/patologia , Vasos Retinianos/citologia , Retinopatia da Prematuridade/induzido quimicamente , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologia
12.
Nihon Yakurigaku Zasshi ; 155(2): 87-92, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115484

RESUMO

Glaucoma, progressive optic neuropathy, is the first cause of blindness in Japan. Blindness in this disease is induced by damages or degeneration of retinal ganglion cells (RGCs), retinal neurons transmit visual information to brain. An elevated intraocular pressure (IOP) is widely recognized as one of the most important risk factors and that IOP directly damages RGCs by mechanical stress, however, accumulating evidences have shown that a majority of Japanese patients for primary open angle glaucoma shows normal level of IOP. Thus, new target for glaucoma pathology is emerged. In this issue, we introduce potential roles of glial cells for pathogenesis of glaucoma. In the CNS, reactive gliosis has been recognized in a variety of neurodegenerative diseases. Such glial activation is also found in retinae of human glaucoma patients and animal models. Importantly, glial activation precedes RGS degeneration, indicating the possibility that reactive glial cells actively contribute to pathogenesis of glaucoma. In this issue, we will focus on macroglial cells such as Muller cells and astrocytes, and discuss their roles in glaucoma.


Assuntos
Glaucoma/patologia , Neuroglia/patologia , Retina/patologia , Células Ganglionares da Retina/patologia , Animais , Astrócitos/patologia , Modelos Animais de Doenças , Células Ependimogliais/patologia , Humanos , Pressão Intraocular , Retina/citologia
13.
Cell Prolif ; 53(3): e12781, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035016

RESUMO

Central nervous system (CNS) maintains a high level of metabolism, which leads to the generation of large amounts of free radicals, and it is also one of the most vulnerable organs to oxidative stress. Emerging evidences have shown that, as the key homeostatic cells in CNS, astrocytes are deeply involved in multiple aspects of CNS function including oxidative stress regulation. Besides, the redox level in CNS can in turn affect astrocytes in morphology and function. The complex and multiple roles of astrocytes indicate that their correct performance is crucial for the normal functioning of the CNS, and its dysfunction may result in the occurrence and progression of various neurological disorders. To date, the influence of astrocytes in CNS oxidative stress is rarely reviewed. Therefore, in this review we sum up the roles of astrocytes in redox regulation and the corresponding mechanisms under both normal and different pathological conditions.


Assuntos
Astrócitos/metabolismo , Doenças do Sistema Nervoso/metabolismo , Estresse Oxidativo , Animais , Astrócitos/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Progressão da Doença , Humanos , Doenças do Sistema Nervoso/patologia , Oxirredução
14.
Nature ; 578(7796): 593-599, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32051591

RESUMO

Multiple sclerosis is a chronic inflammatory disease of the CNS1. Astrocytes contribute to the pathogenesis of multiple sclerosis2, but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.


Assuntos
Astrócitos/patologia , Sistema Nervoso Central/patologia , Inflamação/patologia , Fator de Transcrição MafG/genética , Proteínas Repressoras/genética , Animais , Antioxidantes/metabolismo , Astrócitos/metabolismo , Sistema Nervoso Central/metabolismo , Metilação de DNA , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Inflamação/genética , Masculino , Metionina Adenosiltransferase/genética , Camundongos , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Fator 2 Relacionado a NF-E2/genética , Análise de Sequência de RNA , Transdução de Sinais , Transcrição Genética
15.
Neurology ; 94(13): e1353-e1364, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32001514

RESUMO

OBJECTIVES: Alzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations. METHODS: We mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing. RESULTS: WM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high-WM-TSA (n = 9) and low-WM-TSA (n = 74) pathology signature. The high-WM-TSA group scored significantly worse in language but not in other cognitive domains. CONCLUSIONS: The negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.


Assuntos
Doença de Alzheimer/patologia , Astrócitos/patologia , Transtornos da Linguagem/etiologia , Comportamento Espacial/fisiologia , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Encéfalo/patologia , Estudos Transversais , Feminino , Humanos , Transtornos da Linguagem/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo
16.
Stroke ; 51(3): 967-974, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32019481

RESUMO

Background and Purpose- Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods- Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15tg). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results- In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1ß, and TNF-α is markedly increased in GFAP-IL-15tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15tg mice. Conclusions- Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.


Assuntos
Astrócitos/imunologia , Lesões Encefálicas/imunologia , Hemorragia Cerebral/imunologia , Interleucina-15/imunologia , Microglia/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/patologia , Lesões Encefálicas/etiologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Feminino , Humanos , Interleucina-15/genética , Masculino , Camundongos , Camundongos Transgênicos , Microglia/patologia
17.
Curr Pharm Biotechnol ; 21(10): 955-963, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32039676

RESUMO

BACKGROUND: Glial Maturation Factor Beta (GMFB) is a highly conserved brain-enriched protein implicated in immunoregulation, neuroplasticity and apoptosis, processes central to neural injury and repair following cerebral ischaemia. Therefore, we examined if changes in neurocellular GMFB expression and release can be used to assess brain injury following ischaemia. METHODS AND RESULTS: Immunofluorescence staining, Western blotting, immunohistochemistry and ELISA were used to measure GMFB in cultured neurons and astrocytes, rat brain tissues and plasma samples from stroke model rats and stroke patients, while cell viability assays, TTC staining and micro- PET were used to assess neural cell death and infarct severity. Immunofluorescence and immunohistochemistry revealed GMFB expression mainly in astrocyte and neuronal nuclei but also in neuronal axons and dendrites. Free GMFB concentration increased progressively in the culture medium during hypoxia-hypoglycaemia treatment. Plasma GMFB concentration increased in rats subjected to middle cerebral artery occlusion (MCAO, a model of stroke-reperfusion) and in stroke patients. Plasma GMFB in MCAO model rats was strongly correlated with infarct size (R2=0.9582). Plasma GMFB concentration was also markedly elevated in stroke patients within 24 h of onset and remained elevated for more than one week. Conversely, plasma GMFB elevations were not significant in myocardial infarct patients and stroke patients without infarction. CONCLUSION: GMFB has the prerequisite stability, expression specificity and response dynamics to serve as a reliable indicator of ischaemic injury in animal models and stroke patients. Plasma GMFB may be a convenient non-invasive adjunct to neuroimaging for stroke diagnosis and prognosis.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Infarto Cerebral/sangue , Fator de Maturação da Glia/sangue , Neurônios/metabolismo , Adulto , Animais , Apoptose , Astrócitos/patologia , Encéfalo/patologia , Estudos de Casos e Controles , Morte Celular , Células Cultivadas , Infarto Cerebral/metabolismo , Infarto Cerebral/patologia , Modelos Animais de Doenças , Feminino , Fator de Maturação da Glia/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Valor Preditivo dos Testes , Ratos , Ratos Sprague-Dawley
18.
Proc Natl Acad Sci U S A ; 117(9): 5028-5038, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071226

RESUMO

The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMRß knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMRß KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.


Assuntos
Astrócitos/metabolismo , Oncostatina M/metabolismo , Remielinização/fisiologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Astrócitos/patologia , Axônios , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Bainha de Mielina , Células Precursoras de Oligodendrócitos , Inibidor Tecidual de Metaloproteinase-1/genética
19.
FASEB J ; 34(2): 2425-2435, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31907998

RESUMO

Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/diabetes and AD significantly reduce life expectancy. We generated AppNL-F/wt knock-in; ob/ob mice by crossing AppNL-F/wt knock-in mice and ob/ob mice to investigate whether amyloid-ß (Aß) affects the lifespan of ob/ob mice. AppNL-F/wt knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, AppNL-F/wt knock-in mice, and ob/ob mice. Notably, the Aß42 levels were increased at minimum levels before deposition in AppNL-F/wt knock-in mice and AppNL-F/wt knock-in; ob/ob mice at 18 months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in AppNL-F/wt knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and AppNL-F/wt knock-in; ob/ob mice. The increase in GFAP levels was not observed in young AppNL-F/wt knock-in; ob/ob mice. Thus, the increased Aß42 levels may decrease the lifespan of ob/ob mice, which is associated with the dysregulation of microglia and astrocytes in an age-dependent manner. Based on these findings, the imbalance in these neuroinflammatory cells may provide a clue to the mechanisms by which the interaction between obesity/diabetes and early AD reduces life expectancy.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Longevidade , Microglia/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Astrócitos/patologia , Técnicas de Introdução de Genes , Camundongos , Camundongos Knockout , Camundongos Obesos , Microglia/patologia , Fragmentos de Peptídeos/genética
20.
Rev. méd. Panamá ; 40(1): 14-20, ene.2020. ilus, tab
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1099573

RESUMO

Introducción: Los gliomas son tumores malignos altamente celulares del sistema ner­ vioso central. Su grado histológico preoperatorio es de utilidad en el manejo quirúrgico, por lo que la resonancia magnética con secuencias avanzadas intenta brindar mayor información tumoral. Objetivo: Relacionar el coeficiente aparente de difusión (CAD) y celularidad de los gliomas de pacientes entre enero 2015 a diciembre 2017. Metodo­ logía: Retrospectivamente se obtuvieron de archivos clínicos la edad, sexo, tipo, grado histológico y sitio anatómico. Se calculó el CAD en 5mm 2 en los estudios de resonancia magnética preoperatorias y se utilizó las laminillas para conteo de celularidad en 5mm 2 digitalmente. Se utilizó análisis estadísticos descriptivos y coeficiente de correlación entre CDA con celularidad. Se utilizaron valores de p < 0.05 para significancia estadís­ tica. Resultados: 46 casos fueron incluidos, 56.5% fueron hombres. El rango de 41­64 años fueron los más afectados. El glioblastoma fue el tipo histológico más frecuente (47.8%), así como los gliomas de alto grado (73.9%). El 95.7% fueron supratentoriales. La celularidad promedio fue de 3970 ± 2900 vs 2436 ± 948 núcleos/5mm 2 (p = 0.13), con valores promedio de CDA mínimo de 0.813 x 10­3 ± 0.229 mm 2 /s vs 1.052 x 10­3 ± 0.196 mm 2 /s (p = 0.002), para los gliomas de alto y bajo grado respectivamente. La co­ rrelación entre CDA y celularidad fue débil (R = ­ 0.13, p = 0.37). Conclusión: Existe co­ rrelación débil inversamente proporcional entre el CDA y la celularidad con distinción de gliomas de bajo y alto grado con valores de CDA mínimos


Introduction: Gliomas are highly cellular malignant tumors of the central nervous sys­ tem. Its preoperative histological grade is useful in surgical management, so magnetic resonance imaging with advanced sequences tries to provide more tumor information. Objective: Correlate apparent diffusion coefficient (ADC) and cellularity of gliomas of patients between January 2015 to December 2017. Methodology: Data of age, sex, ty­ pe, histologic grade and anatomic site were retrospectively obtained from clinical archi­ ves. The preoperative magnetic resonance ADC was calculated in a 5 mm 2 region of interest and the microscope slides were used for the cellularity digitally count in 5 mm 2 . Descriptive statistical analysis and correlation coefficient between ADC and cellularity were used. Values of p <0.05 were used for statistical significance. Results: 46 cases were included, 56.5% were men. The 41­64 years ranges were the most affected. Glio­ blastoma was the most frequent histological type (47.8%), as well as high grade glio­ mas (73.9%). 95.7% were supratentorial. The average cellularity was 3970 ± 2900 vs 2436 ± 948 nuclei/ 5mm 2 (p = 0.13), with average minimum ADC values of 0.813 x 10­3 ± 0.229 mm 2 /s vs 1052 x 10­3 ± 0.196 mm 2 /s (p = 0.002), for high­ and low­grade glio­ mas, respectively. The correlation between ADC and cellularity was weak (R = ­ 0.13, p = 0.37). Conclusions: There is a weak inversely proportional correlation between ADC and cellularity. With distinction of low­ and high­grade gliomas with minimum ADC values


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Astrócitos/patologia , Glioma/epidemiologia , Oligodendroglioma/epidemiologia , Imagem por Ressonância Magnética/métodos , Glioblastoma/fisiopatologia
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