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1.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671472

RESUMO

To reveal the pathomechanisms of glaucoma, a common cause of blindness, suitable animal models are needed. As previously shown, retinal ganglion cell and optic nerve degeneration occur in ßB1-CTGF mice. Here, we aimed to determine possible apoptotic mechanisms and degeneration of different retinal cells. Hence, retinae were processed for immunohistology (n = 5-9/group) and quantitative real-time PCR analysis (n = 5-7/group) in 5- and 10-week-old ßB1-CTGF and wildtype controls. We noted significantly more cleaved caspase 3+ cells in ßB1-CTGF retinae at 5 (p = 0.005) and 10 weeks (p = 0.02), and a significant upregulation of Casp3 and Bax/Bcl2 mRNA levels (p < 0.05). Furthermore, more terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL+) cells were detected in transgenic mice at 5 (p = 0.03) and 10 weeks (p = 0.02). Neurofilament H staining (p = 0.01) as well as Nefh (p = 0.02) and Tubb3 (p = 0.009) mRNA levels were significantly decreased at 10 weeks. GABAergic synapse intensity was lower at 5 weeks, while no alterations were noted at 10 weeks. The glutamatergic synapse intensity was decreased at 5 (p = 0.007) and 10 weeks (p = 0.01). No changes were observed for bipolar cells, photoreceptors, and macroglia. We conclude that apoptotic processes and synapse loss precede neuronal death in this model. This slow progression rate makes the ßB1-CTGF mice a suitable model to study primary open-angle glaucoma.


Assuntos
Apoptose , Fator de Crescimento do Tecido Conjuntivo/genética , Animais , Contagem de Células , Camundongos Transgênicos , Modelos Animais , Proteínas de Neurofilamentos/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Células Bipolares da Retina/patologia , Células Ganglionares da Retina/patologia , Sinapses/patologia
2.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668516

RESUMO

While microglia have been established as critical mediators of synaptic plasticity, the molecular signals underlying this process are still being uncovered. Increasing evidence suggests that microglia utilize these signals in a temporally and regionally heterogeneous manner. Subsequently, it is necessary to understand the conditions under which different molecular signals are employed by microglia to mediate the physiological process of synaptic remodeling in development and adulthood. While the microglial purinergic receptor P2Y12 is required for ocular dominance plasticity, an adolescent form of experience-dependent plasticity, it remains unknown whether P2Y12 functions in other forms of plasticity at different developmental time points or in different brain regions. Using a combination of ex vivo characterization and behavioral testing, we examined how the loss of P2Y12 affects developmental processes and behavioral performance in adulthood in mice. We found P2Y12 was not required for an early form of plasticity in the developing visual thalamus and did not affect microglial migration into barrels in the developing somatosensory cortex. In adult mice, however, the loss of P2Y12 resulted in alterations in recognition and social memory, as well as anxiety-like behaviors, suggesting that while P2Y12 is not a universal regulator of synaptic plasticity, the loss of P2Y12 is sufficient to cause functional defects.


Assuntos
Ansiedade/metabolismo , Comportamento Animal , Encéfalo/metabolismo , Plasticidade Neuronal , Receptores Purinérgicos P2Y12/deficiência , Sinapses/metabolismo , Animais , Ansiedade/genética , Ansiedade/patologia , Encéfalo/patologia , Memória , Camundongos , Camundongos Knockout , Receptores Purinérgicos P2Y12/metabolismo , Sinapses/genética , Sinapses/patologia
3.
J Vis Exp ; (167)2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33554966

RESUMO

It has been well studied that the EcoHIV infected mouse model is of significant utility in investigating HIV associated neurological complications. Establishment of the EcoHIV infected rat model for studies of drug abuse and neurocognitive disorders, would be beneficial in the study of neuroHIV and HIV-1 associated neurocognitive disorders (HAND). In the present study, we demonstrate the successful creation of a rat model of active HIV infection using chimeric HIV (EcoHIV). First, the lentiviral construct of EcoHIV was packaged in cultured 293 FT cells for 48 hours. Then, the conditional medium was concentrated and titered. Next, we performed bilateral stereotaxic injections of the EcoHIV-EGFP into F344/N rat brain tissue. One week after infection, EGFP fluorescence signals were detected in the infected brain tissue, indicating that EcoHIV successfully induces an active HIV infection in rats. In addition, immunostaining for the microglial cell marker, Iba1, was performed. The results indicated that microglia were the predominant cell type harboring EcoHIV. Furthermore, EcoHIV rats exhibited alterations in temporal processing, a potential underlying neurobehavioral mechanism of HAND as well as synaptic dysfunction eight weeks after infection. Collectively, the present study extends the EcoHIV model of HIV-1 infection to the rat offering a valuable biological system to study HIV-1 viral reservoirs in the brain as well as HAND and associated comorbidities such as drug abuse.


Assuntos
Encéfalo/patologia , Encéfalo/virologia , Infecções por HIV/patologia , HIV-1/fisiologia , Animais , Quimera , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/metabolismo , Infecções por HIV/complicações , Humanos , Masculino , Camundongos , Ratos Endogâmicos F344 , Técnicas Estereotáxicas , Sinapses/patologia , Fatores de Tempo , Replicação Viral
4.
Cell Stem Cell ; 28(2): 331-342.e5, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33450186

RESUMO

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.


Assuntos
Apolipoproteínas E/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Células-Tronco Pluripotentes Induzidas/virologia , Tropismo/fisiologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Antivirais/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Astrócitos/virologia , Diferenciação Celular , Chlorocebus aethiops , Humanos , Degeneração Neural/patologia , Neuritos/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/virologia , Organoides/efeitos dos fármacos , Organoides/patologia , Organoides/virologia , Isoformas de Proteínas/metabolismo , Sinapses/patologia , Células Vero
5.
Nat Neurosci ; 24(3): 355-367, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495636

RESUMO

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.


Assuntos
Cálcio/metabolismo , Córtex Cerebral/metabolismo , Inflamação/metabolismo , Esclerose Múltipla/metabolismo , Fagócitos/metabolismo , Sinapses/metabolismo , Animais , Córtex Cerebral/patologia , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Inflamação/patologia , Camundongos , Microglia/metabolismo , Esclerose Múltipla/patologia , Neurônios/metabolismo , Neurônios/patologia , Sinapses/patologia
6.
Arch Oral Biol ; 123: 105039, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33454419

RESUMO

OBJECTIVE: Prolonged mild stress due to tooth loss leads to morphologic and functional alterations of the hippocampus, as well as cognitive memory impairments in aged animals. An enriched environment improves stress-induced hippocampus-dependent cognitive impairments. The potential mechanisms underlying the beneficial effects of an enriched environment, however, remain unclear. In the present study, we investigated whether an enriched environment affects morphologic remodeling of the hippocampal myelin, synapses, and spatial learning deficits caused by tooth loss in aged senescence-accelerated mouse strain P8 (SAMP8) mice. DESIGN: SAMP8 mice (8 months old) with either teeth intact or teeth extracted were raised in a standard or enriched environment for three weeks. Spatial learning and memory ability was evaluated in a Morris water maze test. The morphologic features of the myelin sheath and synapses in the hippocampus were investigated by electron microscopy. RESULTS: Mice with tooth loss had a thinner myelin sheaths and shorter postsynaptic densities in the hippocampal CA1 region, and impaired hippocampus-dependent spatial learning ability. Exposure to an enriched environment ameliorated the hypomyelination and synaptic alterations, and spatial learning and memory impairments induced by tooth loss in aged SAMP8 mice. CONCLUSION: Our findings indicate that an enriched environment ameliorates hippocampal hypomyelination and synapse morphologic abnormalities, as well as learning deficits induced by tooth loss in aged SAMP8 mice.


Assuntos
Meio Ambiente , Hipocampo/fisiopatologia , Transtornos da Memória/etiologia , Bainha de Mielina , Sinapses/patologia , Perda de Dente/complicações , Animais , Aprendizagem em Labirinto , Camundongos
7.
Nat Neurosci ; 24(2): 214-224, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33353966

RESUMO

The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.


Assuntos
Comportamento Animal , Complemento C4/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Sinapses/patologia , Animais , Complemento C4/biossíntese , Espinhas Dendríticas/patologia , Depressão/psicologia , Feminino , Dosagem de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/patologia , Rede Nervosa/patologia , Desempenho Psicomotor , Esquizofrenia/patologia , Sinaptossomos/patologia
8.
PLoS One ; 15(12): e0242773, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338084

RESUMO

Autism Spectrum Disorder (ASD) is a heterogeneous disorder that is often accompanied with many co-morbidities. Recent genetic studies have identified various pathways from hundreds of candidate risk genes with varying levels of association to ASD. However, it is unknown which pathways are specific to the core symptoms or which are shared by the co-morbidities. We hypothesised that critical ASD candidates should appear widely across different scoring systems, and that comorbidity pathways should be constituted by genes expressed in the relevant tissues. We analysed the Simons Foundation for Autism Research Initiative (SFARI) database and four independently published scoring systems and identified 292 overlapping genes. We examined their mRNA expression using the Genotype-Tissue Expression (GTEx) database and validated protein expression levels using the human protein atlas (HPA) dataset. This led to clustering of the overlapping ASD genes into 2 groups; one with 91 genes primarily expressed in the central nervous system (CNS geneset) and another with 201 genes expressed in both CNS and peripheral tissues (CNS+PT geneset). Bioinformatic analyses showed a high enrichment of CNS development and synaptic transmission in the CNS geneset, and an enrichment of synapse, chromatin remodelling, gene regulation and endocrine signalling in the CNS+PT geneset. Calcium signalling and the glutamatergic synapse were found to be highly interconnected among pathways in the combined geneset. Our analyses demonstrate that 2/3 of ASD genes are expressed beyond the brain, which may impact peripheral function and involve in ASD co-morbidities, and relevant pathways may be explored for the treatment of ASD co-morbidities.


Assuntos
Transtorno do Espectro Autista/genética , Sinalização do Cálcio/genética , Epilepsia/genética , Redes Reguladoras de Genes , Proteínas do Tecido Nervoso/genética , Transtornos da Personalidade/genética , Comportamento Autodestrutivo/genética , Adulto , Idoso , Atlas como Assunto , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Cromatina/metabolismo , Cromatina/ultraestrutura , Comorbidade , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Epilepsia/diagnóstico , Epilepsia/metabolismo , Epilepsia/patologia , Feminino , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/patologia , Transtornos da Personalidade/diagnóstico , Transtornos da Personalidade/metabolismo , Transtornos da Personalidade/patologia , Comportamento Autodestrutivo/diagnóstico , Comportamento Autodestrutivo/metabolismo , Comportamento Autodestrutivo/patologia , Sinapses/metabolismo , Sinapses/patologia , Sinapses/ultraestrutura , Transmissão Sináptica , Transcrição Genética
9.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322202

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid ß (Aß) in the brain. Although several studies reported possible mechanisms involved in Aß pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aß-responsive gene involved in Aß cytotoxicity. However, we still do not know how Aß increases the level of REDD1 and whether REDD1 mediates Aß-induced synaptic dysfunction. To elucidate this, we examined the effect of Aß on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aß-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aß-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aß injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aß-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aß may increase REDD1 translation rather than transcription. Aß activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aß-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aß blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aß-induced synaptic deficits. REDD1 shRNA also blocked Aß-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aß pathology and could be a target for AD therapy.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/farmacologia , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transtornos da Memória/metabolismo , Sinapses/metabolismo , Fatores de Transcrição/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Anisomicina/farmacologia , Dactinomicina/farmacologia , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Transtornos da Memória/genética , Transtornos da Memória/patologia , Testes de Memória e Aprendizagem , Camundongos , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , RNA Interferente Pequeno , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/genética , Sinapses/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Regulação para Cima
10.
Int J Mol Sci ; 22(1)2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374598

RESUMO

The correlation between dysfunction in the glutamatergic system and neuropsychiatric disorders, including schizophrenia and autism spectrum disorder, is undisputed. Both disorders are associated with molecular and ultrastructural alterations that affect synaptic plasticity and thus the molecular and physiological basis of learning and memory. Altered synaptic plasticity, accompanied by changes in protein synthesis and trafficking of postsynaptic proteins, as well as structural modifications of excitatory synapses, are critically involved in the postnatal development of the mammalian nervous system. In this review, we summarize glutamatergic alterations and ultrastructural changes in synapses in schizophrenia and autism spectrum disorder of genetic or drug-related origin, and briefly comment on the possible reversibility of these neuropsychiatric disorders in the light of findings in regular synaptic physiology.


Assuntos
Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/metabolismo , Ácido Glutâmico/metabolismo , Receptores de Glutamato/metabolismo , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Sinapses/metabolismo , Sinapses/ultraestrutura , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Mitocôndrias/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Roedores , Sinapses/patologia
11.
Science ; 370(6512): 66-69, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004513

RESUMO

Dementia is a rapidly rising global health crisis that silently disables families and ends lives and livelihoods around the world. To date, however, no early biomarkers or effective therapies exist. It is now clear that brain microglia are more than mere bystanders or amyloid phagocytes; they can act as governors of neuronal function and homeostasis in the adult brain. Here, we highlight the fundamental role of microglia as tissue-resident macrophages in neuronal health. Then, we suggest how chronic impairment in microglia-neuron cross-talk may secure the permanence of the failure of synaptic and neuronal function and health in Alzheimer's and Parkinson's diseases. Understanding how to assess and modulate microglia-neuron interactions critical for brain health will be key to developing effective therapies for dementia.


Assuntos
Doença de Alzheimer/patologia , Amiloide/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Doença de Parkinson/patologia , Sinapses/patologia , Animais , Comunicação Celular , Humanos , Camundongos , Neurônios/metabolismo , Sinaptossomos/patologia , alfa-Sinucleína/metabolismo
13.
PLoS One ; 15(9): e0239584, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966331

RESUMO

Familial forms of Alzheimer's disease (AD) are caused by mutations in the presenilin genes or in the gene encoding for the amyloid precursor protein (APP). Proteolytic cleavage of APP generates the ß-amyloid peptide (Aß), which aggregates into amyloid plaques, one of the major hallmarks of AD. APP mutations within the Aß sequence, so-called intra-Aß mutations, cluster around position E693 of APP, which corresponds to position E22 in the Aß sequence. One of these mutations is the Osaka mutation, E693Δ, which has unique aggregation properties with patients showing unusually low brain amyloid levels on amyloid PET scans. Despite intense research on the pathomechanisms of different intra-Aß mutants, our knowledge is limited due to controversial findings in various studies. Here, we investigated in an ex vivo experimental system the neuro- and synaptotoxic properties of two intra-Aß mutants with different intrinsic aggregation propensities, the Osaka mutation E22Δ and the Arctic mutation E22G, and compared them to wild-type (wt) Aß. Experiments in hippocampal slice cultures from transgenic mice were complemented by treating wild-type slices with recombinantly produced Aß40 or Aß42 containing the respective intra-Aß mutations. Our analyses revealed that wt Aß and E22G Aß, both recombinant and transgenic, caused a loss of dendritic spines along with an increase in tau phosphorylation and tau-dependent neurodegeneration. In all experiments, the 42-residue variants of wt and E22G Aß showed stronger effects than the respective Aß40 isoforms. In contrast, E22Δ Aß neither reduced dendritic spine density nor resulted in increased tau phosphorylation or neuronal cell death in our ex vivo system. Our findings suggest that the previously reported major differences in the aggregation kinetics between E22G and E22Δ Aß are likely reflected in different disease pathomechanisms.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Proteínas Mutantes/genética , Mutação , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Morte Celular , Espinhas Dendríticas/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Técnicas In Vitro , Cinética , Camundongos , Camundongos Transgênicos , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fosforilação , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sinapses/patologia
14.
Cancer Cell ; 37(6): 786-799.e5, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32516589

RESUMO

Generation of tumor-infiltrating lymphocytes begins when tumor antigens reach the lymph node (LN) to stimulate T cells, yet we know little of how tumor material is disseminated among the large variety of antigen-presenting dendritic cell (DC) subsets in the LN. Here, we demonstrate that tumor proteins are carried to the LN within discrete vesicles inside DCs and are then transferred among DC subsets. A synapse is formed between interacting DCs and vesicle transfer takes place in the absence of free exosomes. DCs -containing vesicles can uniquely activate T cells, whereas DCs lacking them do not. Understanding this restricted sharing of tumor identity provides substantial room for engineering better anti-tumor immunity.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos de Neoplasias/imunologia , Células Dendríticas/imunologia , Melanoma Experimental/imunologia , Células Mieloides/imunologia , Sinapses/imunologia , Linfócitos T/imunologia , Animais , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Masculino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/citologia , Células Mieloides/metabolismo , Receptores CCR2/fisiologia , Receptores CCR7/fisiologia , Sinapses/metabolismo , Sinapses/patologia , Linfócitos T/citologia , Linfócitos T/metabolismo
15.
Neurology ; 95(8): e953-e961, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586895

RESUMO

OBJECTIVE: To assess the ability of a combination of synaptic CSF biomarkers to separate Alzheimer disease (AD) and non-AD disorders and to help in the differential diagnosis between neurocognitive diseases. METHODS: This was a retrospective cross-sectional monocentric study. All participants explored with CSF assessments for neurocognitive decline were invited to participate. After complete clinical and imaging evaluations, 243 patients were included. CSF synaptic (GAP-43, neurogranin, SNAP-25 total, SNAP-25aa40, synaptotagmin-1) and AD biomarkers were blindly quantified with ELISA or mass spectrometry. Statistical analysis compared CSF levels between the various groups of AD dementias (n = 81), mild cognitive impairment (MCI)-AD (n = 30), other MCI (n = 49), other dementias (OD) (n = 49), and neurologic controls (n = 35) and their discriminatory powers. RESULTS: All synaptic biomarkers were significantly increased in patients with MCI-AD and AD-dementia compared to the other groups. All synaptic biomarkers could efficiently discriminate AD dementias from OD (AUC ≥0.80). All but synaptotagmin were also able to discriminate patients with MCI-AD from controls (area under the curve [AUC] ≥0.85) and those with AD dementias from controls (AUC ≥0.80). Overall, CSF SNAP-25aa40 had the highest discriminative power (AUC 0.93 between patients with AD dementias and controls or OD, AUC 0.90 between those with MCI-AD and controls). Higher levels were associated with 2 alleles of APOE ε4. CONCLUSION: All synaptic biomarkers tested had a good discriminatory power to distinguish patients with AD abnormal CSF from those with non-AD disorders. SNAP25aa40 demonstrated the highest power to discriminate AD CSF-positive patients from patients without AD and neurologic controls in this cohort. CLASSIFICATION OF EVIDENCE: This retrospective study provides Class II evidence that CSF synaptic biomarkers discriminate patients with AD from those without AD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Idoso , Estudos Transversais , Diagnóstico Diferencial , Feminino , Proteína GAP-43/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Neurogranina/líquido cefalorraquidiano , Estudos Retrospectivos , Sensibilidade e Especificidade , Sinapses/metabolismo , Sinapses/patologia , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Sinaptotagmina I/líquido cefalorraquidiano
16.
Nat Commun ; 11(1): 2261, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385304

RESUMO

Prolonged exposure to negative stressors could be harmful if a subject cannot respond appropriately. Strategies evolved to respond to stress, including repetitive displacement behaviours, are important in maintaining behavioural homoeostasis. In rodents, self-grooming is a frequently observed repetitive behaviour believed to contribute to post-stress de-arousal with adaptive value. Here we identified a rat limbic di-synaptic circuit that regulates stress-induced self-grooming with positive affective valence. This circuit links hippocampal ventral subiculum to ventral lateral septum (LSv) and then lateral hypothalamus tuberal nucleus. Optogenetic activation of this circuit triggers delayed but robust excessive grooming with patterns closely resembling those evoked by emotional stress. Consistently, the neural activity of LSv reaches a peak before emotional stress-induced grooming while inhibition of this circuit significantly suppresses grooming triggered by emotional stress. Our results uncover a previously unknown limbic circuitry involved in regulating stress-induced self-grooming and pinpoint a critical role of LSv in this ethologically important behaviour.


Assuntos
Emoções/fisiologia , Sistema Límbico/fisiopatologia , Rede Nervosa/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Cálcio/metabolismo , Asseio Animal , Hipocampo/fisiopatologia , Masculino , Modelos Biológicos , Neurônios/patologia , Optogenética , Probabilidade , Ratos Sprague-Dawley , Sinapses/patologia
17.
J Neuropathol Exp Neurol ; 79(6): 585-591, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32388566

RESUMO

Hyperphosphorylation, nuclear depletion, and aggregation of TDP-43 in ubiquitinated inclusions is a hallmark of frontotemporal lobar degeneration (FTLD-TDP). Evidence of potential spread of TDP-43 along synaptic connections in the human is largely limited to qualitative and semiquantitative observations. We quantitatively investigated potential transsynaptic propagation of TDP-43 across the well-established chain of single synaptic connections of the hippocampus. Hippocampi from 5 participants with clinical diagnoses of primary progressive aphasia and 2 participants with behavioral variant frontotemporal dementia, all with postmortem diagnoses of FTLD-TDP, were examined. TDP-43-positive mature (darkly stained) and pre-inclusions (diffuse puncta or fibrillar staining) in the granule cell layer of dentate gyrus (DG) and pyramidal cell layers of Cornu Ammonis (CA)3, CA2, and CA1 were quantified using unbiased stereology. The density of mature TDP-43 inclusions was higher in the DG than in the CA fields (p < 0.05). There were no differences in inclusion densities across the CA fields. TDP-43 pre-inclusions densities were not different across the 4 subregions. There was significantly higher preinclusion density than mature inclusions in CA3, but not in other subregions. Analysis of normalized total counts in place of densities revealed virtually identical results. Our finding of greatest mature inclusion deposition in the DG, coupled with more preinclusions than mature inclusions at the next relay station (CA3), and reduced densities of both in CA2-CA1, provide evidence in support of a sequential transsynaptic propagation mechanism of TDP-43 aggregates.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/patologia , Hipocampo/patologia , Agregação Patológica de Proteínas/patologia , Sinapses/patologia , Idoso , Afasia Primária Progressiva/metabolismo , Afasia Primária Progressiva/patologia , Feminino , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/metabolismo , Sinapses/metabolismo
18.
Environ Toxicol ; 35(9): 922-929, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32293791

RESUMO

Excessive fluoride exposure contributes to neurotoxic effects. Emodin exhibits antioxidative functions in the central nervous system (CNS); however, its neuroprotective mechanism against fluoride remains to be elucidated. Our aim was to explore the neuroprotective efficacy and the possible mechanisms of emodin. In our study, synaptic proteins and oxidative stress damage were examined after human neuroblastoma SH-SY5Y cells were treated with high doses of NaF for 24 hours. Moreover, pretreatment with emodin was used to shed light on the neuroprotective effects in NaF-induced toxicity in SH-SY5Y cells. We found that NaF significantly lowered the protein expressions of SNAP 25, synaptophysin and PSD 95 in SH-SY5Y cells. In addition, NaF exposure increased the protein expression of p-ERK1/2 and decreased the protein expressions of Nrf2 and HO-1, as well as facilitated increasing ROS, 4-hydroxynonenal (4-HNE), and 8-Hydroxy-2'-deoxyguanosine (8-OHdG). Pretreatment with emodin significantly recovered these alterations caused by NaF. These data implied that the neuroprotective effects of emodin and pointed to the promising utilization for protecting against neurotoxicity induced by fluoride.


Assuntos
Emodina/farmacologia , Fluoretos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neuroblastoma/metabolismo , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Sinapses/metabolismo , Sinapses/patologia , Sinaptofisina/metabolismo
19.
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
20.
Nat Commun ; 11(1): 1369, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170075

RESUMO

The integration and cooperation of mechanoreceptors, neurons and synapses in somatosensory systems enable humans to efficiently sense and process tactile information. Inspired by biological somatosensory systems, we report an optoelectronic spiking afferent nerve with neural coding, perceptual learning and memorizing capabilities to mimic tactile sensing and processing. Our system senses pressure by MXene-based sensors, converts pressure information to light pulses by coupling light-emitting diodes to analog-to-digital circuits, then integrates light pulses using a synaptic photomemristor. With neural coding, our spiking nerve is capable of not only detecting simultaneous pressure inputs, but also recognizing Morse code, braille, and object movement. Furthermore, with dimensionality-reduced feature extraction and learning, our system can recognize and memorize handwritten alphabets and words, providing a promising approach towards e-skin, neurorobotics and human-machine interaction technologies.


Assuntos
Vias Aferentes/fisiologia , Aprendizagem/fisiologia , Sistema Nervoso Periférico/fisiologia , Tato/fisiologia , Potenciais de Ação , Biomimética , Humanos , Mecanorreceptores/fisiologia , Movimento , Neurônios/patologia , Pele/inervação , Sinapses/patologia
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