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1.
Nat Commun ; 12(1): 1423, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658509

RESUMEN

In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.


Asunto(s)
Epilepsia/fisiopatología , Hipocampo/fisiopatología , Neurogénesis/fisiología , Animales , Calcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacología , Modelos Animales de Enfermedad , Electroencefalografía , Epilepsia del Lóbulo Temporal/fisiopatología , Femenino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Pilocarpina/farmacología , Retroviridae/genética , Convulsiones/fisiopatología , Ácido gamma-Aminobutírico/metabolismo
2.
Cells ; 10(2)2021 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668514

RESUMEN

As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.


Asunto(s)
/complicaciones , Vesículas Extracelulares/patología , Enfermedades del Sistema Nervioso/etiología , Adulto , Anciano , Péptidos beta-Amiloides/análisis , Biomarcadores/análisis , Biomarcadores/sangre , /patología , Femenino , Humanos , Inmunoglobulina G/sangre , Interleucina-4/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso/patología , Proteínas de Neurofilamentos/análisis , Neurogranina/análisis , Neuronas/patología , Proteínas tau/análisis
3.
Int J Nanomedicine ; 16: 1423-1434, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33654394

RESUMEN

Background: Interleukin-1ß (IL-1)-treated mesenchymal stem cells (MSCs) and IL-1-MSCs-conditioned medium (CM) exert anti-inflammatory roles. Astrocytes are essential for the modulation of synaptic activity and neuronal homeostasis in the brain. Exosomes are the critical mediators in intercellular communication. However, the mechanism underlying the anti-inflammatory effect of IL-1-treated MSCs remains unknown. Methods: In this study, exosomes (IL-1-Exo) were isolated from IL-1-treated MSCs. In addition, lipopolysaccharide (LPS)-treated hippocampal astrocytes and status epilepticus (SE) mice were treated with IL-1-Exo. Inflammatory activity, astrogliosis, and cognitive performance were measured to determine the effect of IL-1-Exo on inflammation. Results: The results revealed that IL-1-Exo significantly inhibited LPS-induced astrogliosis and inflammatory responses of astrocytes. Also, IL-1-Exo reversed the LPS-induced effect on calcium signaling. The Nrf2 signaling pathway was associated with the effect of IL-1-Exo in LPS-treated astrocytes. Furthermore, IL-1-Exo reduced the inflammatory response and improved the cognitive performance of SE mice. Conclusion: The results suggest that IL-1-Exo inhibited LPS-induced inflammatory responses in astrocytes and SE mice and that the effect of IL-1-Exo was primarily mediated through the Nrf-2 signaling pathway. This study provides a new understanding of the molecular mechanism of inflammation-associated brain diseases and an avenue to develop nanotherapeutic agents for the treatment of inflammatory conditions in the brain.


Asunto(s)
Astrocitos/patología , Exosomas/metabolismo , Hipocampo/patología , Inflamación/terapia , Interleucina-1beta/farmacología , Células Madre Mesenquimatosas/citología , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Animales , Animales Recién Nacidos , Antiinflamatorios/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Conducta Animal/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Exosomas/efectos de los fármacos , Exosomas/ultraestructura , Humanos , Inflamación/patología , Lipopolisacáridos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Transducción de Señal/efectos de los fármacos , Estado Epiléptico/patología
4.
Yonsei Med J ; 62(3): 215-223, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33635011

RESUMEN

PURPOSE: This study aimed to elucidate whether lncRNA ZFAS1 is involved in neuronal apoptosis and inflammation in temporal lobe epilepsy (TLE). MATERIALS AND METHODS: Ninety-six TLE patients were recruited, and their peripheral venous blood was gathered to determine Zfas1 expression with polymerase chain reaction. Neurons were separated from hippocampal tissue of newborn SD rats, and si-Zfas1 or pcDNA3.1-Zfas1 was transfected into the neurons. Inflammatory cytokines released by neurons were determined, and neuronal activities were evaluated through MTT assay, colony formation assay, and flow cytometry. RESULTS: Serum levels of Zfas1 were higher in TLE patients than in healthy controls (p<0.05). Furthermore, Zfas1 expression in neurons was raised by pcDNA3.1-Zfas1 and declined after silencing of Zfas1 (p<0.05). Transfection of pcDNA-Zfas1 weakened the viability and proliferation of neurons and increased neuronal apoptosis (p<0.05). Meanwhile, pcDNA3.1-Zfas1 transfection promoted lipopolysaccharide-induced release of cytokines, including tumor necrosis factor-α, interleukin (IL)-1, IL-6, and intercellular adhesion molecule-1 (p<0.05), and boosted NF-κB activation by elevating the expression of NF-κB p65, pIκBα, and IKKß in neurons (p<0.05). CONCLUSION: Our results indicated that lncRNA ZFAS1 exacerbates epilepsy development by promoting neuronal apoptosis and inflammation, implying ZFAS1 as a promising treatment target for epilepsy.


Asunto(s)
Apoptosis/genética , Epilepsia del Lóbulo Temporal/genética , Inflamación/patología , Neuronas/patología , ARN Largo no Codificante/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Estudios de Casos y Controles , Supervivencia Celular/genética , Niño , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica , Hipocampo/patología , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , Ratas Sprague-Dawley , Transducción de Señal/genética , Adulto Joven
5.
J Vis Exp ; (167)2021 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-33554967

RESUMEN

Excitotoxic necrosis is a leading form of neurodegeneration. This process of regulated necrosis is triggered by the synaptic accumulation of the neurotransmitter glutamate, and the excessive stimulation of its postsynaptic receptors. However, information on the subsequent molecular events that culminate in the distinct neuronal swelling morphology of this type of neurodegeneration is lacking. Other aspects, such as changes in specific subcellular compartments, or the basis for the differential cellular vulnerability of distinct neuronal subtypes, remain under-explored. Furthermore, a range of factors that come into play in studies that use in vitro or ex vivo preparations might modify and distort the natural progression of this form of neurodegeneration. It is therefore important to study excitotoxic necrosis in live animals by monitoring the effects of interventions that regulate the extent of neuronal necrosis in the genetically amenable and transparent model system of the nematode Caenorhabditis elegans. This protocol describes methods of studying excitotoxic necrosis in C. elegans neurons, combining optical, genetic, and molecular analysis. To induce excitotoxic conditions in C. elegans, a knockout of a glutamate transporter gene (glt-3) is combined with a neuronal sensitizing genetic background (nuls5 [Pglr-1::GαS(Q227L)]) to produce glutamate receptor hyperstimulation and neurodegeneration. Nomarski differential interference contrast (DIC), fluorescent, and confocal microscopy in live animals are methods used to quantify neurodegeneration, follow subcellular localization of fluorescently labeled proteins, and quantify mitochondrial morphology in the degenerating neurons. Neuronal Fluorescence Activated Cell Sorting (FACS) is used to distinctly sort at-risk neurons for cell-type specific transcriptomic analysis of neurodegeneration. A combination of live imaging and FACS methods as well as the benefits of the C. elegans model organism allow researchers to leverage this system to obtain reproducible data with a large sample size. Insights from these assays could translate to novel targets for therapeutic intervention in neurodegenerative diseases.


Asunto(s)
Caenorhabditis elegans/citología , Imagenología Tridimensional , Degeneración Nerviosa/diagnóstico por imagen , Degeneración Nerviosa/patología , Neurotoxinas/toxicidad , Envejecimiento/patología , Crianza de Animales Domésticos , Animales , Apoptosis , Tampones (Química) , Caenorhabditis elegans/efectos de los fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Ácido Glutámico/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Necrosis , Neuronas/efectos de los fármacos , Neuronas/patología , Neuroprotección/efectos de los fármacos , ARN/aislamiento & purificación , Factores de Riesgo , Transcriptoma/genética
6.
Nat Commun ; 12(1): 1033, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589615

RESUMEN

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Drogas en Investigación/farmacología , Aprendizaje Automático , Proteínas del Tejido Nervioso/genética , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Medicamentos bajo Prescripción/farmacología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Reposicionamiento de Medicamentos , Drogas en Investigación/química , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Humanos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/química , Nootrópicos/química , Farmacogenética/métodos , Farmacogenética/estadística & datos numéricos , Polifarmacología , Medicamentos bajo Prescripción/química , Cultivo Primario de Células , Índice de Severidad de la Enfermedad
7.
Nat Neurosci ; 24(3): 343-354, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33558694

RESUMEN

Aberrant inflammation in the CNS has been implicated as a major player in the pathogenesis of human neurodegenerative disease. We developed a new approach to derive microglia from human pluripotent stem cells (hPSCs) and built a defined hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular cross-talk along the neuroinflammatory axis in vitro. We used the tri-culture system to model neuroinflammation in Alzheimer's disease with hPSCs harboring the APPSWE+/+ mutation and their isogenic control. We found that complement C3, a protein that is increased under inflammatory conditions and implicated in synaptic loss, is potentiated in tri-culture and further enhanced in APPSWE+/+ tri-cultures due to microglia initiating reciprocal signaling with astrocytes to produce excess C3. Our study defines the major cellular players contributing to increased C3 in Alzheimer's disease and presents a broadly applicable platform to study neuroinflammation in human disease.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Complemento C3/metabolismo , Microglía/metabolismo , Células Madre Pluripotentes/patología , Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Astrocitos/patología , Hematopoyesis/fisiología , Humanos , Inflamación/metabolismo , Inflamación/patología , Microglía/patología , Modelos Biológicos , Neuronas/metabolismo , Neuronas/patología
8.
Hum Immunol ; 82(3): 155-161, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33583639

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to neuronal death in the brain and spinal cord. Over the last decades, evidence has emerged regarding the functional diversity of astrocytes, microglia, and T cells in the central nervous system (CNS), and the role of neuroinflammation in ALS. In this review, we summarize current knowledge regarding neuroinflammation in ALS, both at the level of specific molecular pathways and potential cellular pathways as well as outline questions about the immune mechanisms involved in ALS pathogenesis.


Asunto(s)
Esclerosis Amiotrófica Lateral/inmunología , Encéfalo/patología , Neuroglía/inmunología , Neuronas/patología , Médula Espinal/patología , Linfocitos T/inmunología , Animales , Autoinmunidad , Humanos , Inmunidad Celular , Inflamación Neurogénica , Transducción de Señal
9.
Mol Cell ; 81(6): 1260-1275.e12, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33561390

RESUMEN

DNA methylation is implicated in neuronal biology via the protein MeCP2, the mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 co-repressor complexes to methylated cytosine in the CG dinucleotide, but also to sites of non-CG methylation, which are abundant in neurons. To test the biological significance of the dual-binding specificity of MeCP2, we replaced its DNA binding domain with an orthologous domain from MBD2, which can only bind mCG motifs. Knockin mice expressing the domain-swap protein displayed severe Rett-syndrome-like phenotypes, indicating that normal brain function requires the interaction of MeCP2 with sites of non-CG methylation, specifically mCAC. The results support the notion that the delayed onset of Rett syndrome is due to the simultaneous post-natal accumulation of mCAC and its reader MeCP2. Intriguingly, genes dysregulated in both Mecp2 null and domain-swap mice are implicated in other neurological disorders, potentially highlighting targets of relevance to the Rett syndrome phenotype.


Asunto(s)
Metilación de ADN , Proteína 2 de Unión a Metil-CpG/metabolismo , Neuronas/metabolismo , Animales , Islas de CpG , Técnicas de Sustitución del Gen , Células HeLa , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Transgénicos , Mutación , Células 3T3 NIH , Neuronas/patología , Dominios Proteicos , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Síndrome de Rett/patología
10.
Medicine (Baltimore) ; 100(4): e23873, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33530181

RESUMEN

BACKGROUND: Ischemic stroke is a huge threat to human health globally. Rescuing neurons in the ischemic penumbra (IP) is pivotal after the onset of ischemic stroke, and autophagy is essential to the survival of IP neurons and the development of related pathological processes. As the most common autophagy inhibitor, 3-Methyladenine (3-MA) is widely used in studies related to the mechanism of neuronal autophagy in ischemic stroke; however, there is no consensus has been reached on its effects of neuroprotection or neurodamage, which hinders the development and clinical application of autophagy-targeted therapy strategies for the treatment of ischemic stroke. METHODS: We will search the following electronic bibliographic databases: PubMed, EMBASE, Scopus, Science Direct, and Web of Science. Participant intervention comparator outcomes of this study are as flowing: P, animal models of ischemic stroke; I, received 3-MA treatment merely; C, received only vehicle or sham treatment, or no treatment; O, Primary outcomes are infarct volume; neuro-behavioral scores. Secondary outcomes are cerebral blood flow, blood-brain barrier permeability, cerebral hemorrhage, brain water content. Review Manager 5.3 and Stata 15.1 will be used in data analysis. The characteristics of the studies, the experimental model, and the main results will be described, the quality assessment and the risk of bias assessment will be conducted. A narrative synthesis will be made for the included studies. Besides, if sufficient qualitative data is available, a meta-analysis will be conducted. I2 statistics will be used to assess heterogeneity. DISCUSSION: This systematic review and meta-analysis of the autophagy inhibitor 3-MAs effects on animal models of ischemic stroke can help us to understand whether inhibiting autophagy brings protection or damage to IP neurons; in addition, it also helps to clarify the specific role of autophagy in cerebral infarction. Therefore, this study can provide evidence for the future development of therapy strategies targeting autophagy and bring more hope to patients with ischemic stroke. PROSPERO REGISTRATION NUMBER: CRD42020194262.


Asunto(s)
Adenina/análogos & derivados , Autofagia/efectos de los fármacos , Metaanálisis como Asunto , Revisiones Sistemáticas como Asunto , Adenina/uso terapéutico , Animales , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/patología , Infarto Encefálico/fisiopatología , Protocolos Clínicos , /fisiopatología , Modelos Animales , Neuronas/patología , Proyectos de Investigación
11.
Nat Neurosci ; 24(2): 276-287, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33432193

RESUMEN

Alzheimer's disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus-brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively-from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Corteza Entorrinal/metabolismo , Lóbulo Frontal/metabolismo , Neuronas/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Astrocitos/patología , Corteza Entorrinal/patología , Femenino , Lóbulo Frontal/patología , Humanos , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Neuronas/patología , Proteínas tau/metabolismo
12.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-33440708

RESUMEN

Calbindin-D28k (CB), a calcium-binding protein, mediates diverse neuronal functions. In this study, adult gerbils were fed a normal diet (ND) or exposed to intermittent fasting (IF) for three months, and were randomly assigned to sham or ischemia operated groups. Ischemic injury was induced by transient forebrain ischemia for 5 min. Short-term memory was examined via passive avoidance test. CB expression was investigated in the Cornu Ammonis 1 (CA1) region of the hippocampus via western blot analysis and immunohistochemistry. Finally, histological analysis was used to assess neuroprotection and gliosis (microgliosis and astrogliosis) in the CA1 region. Short-term memory did not vary significantly between ischemic gerbils with IF and those exposed to ND. CB expression was increased significantly in the CA1 pyramidal neurons of ischemic gerbils with IF compared with that of gerbils fed ND. However, the CB expression was significantly decreased in ischemic gerbils with IF, similarly to that of ischemic gerbils exposed to ND. The CA1 pyramidal neurons were not protected from ischemic injury in both groups, and gliosis (astrogliosis and microgliosis) was gradually increased with time after ischemia. In addition, immunoglobulin G was leaked into the CA1 parenchyma from blood vessels and gradually increased with time after ischemic insult in both groups. Taken together, our study suggests that IF for three months increases CB expression in hippocampal CA1 pyramidal neurons; however, the CA1 pyramidal neurons are not protected from transient forebrain ischemia. This failure in neuroprotection may be attributed to disruption of the blood-brain barrier, which triggers gliosis after ischemic insults.


Asunto(s)
Calbindina 1/genética , Ayuno , Expresión Génica , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Animales , Calbindina 1/inmunología , Muerte Celular/genética , Muerte Celular/inmunología , Gerbillinae , Gliosis/etiología , Inmunoglobulina G/inmunología , Masculino , Neuronas/metabolismo , Neuronas/patología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología
13.
Nutr Metab Cardiovasc Dis ; 31(1): 333-343, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33500109

RESUMEN

BACKGROUND AND AIMS: Diabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury. METHODS AND RESULTS: 72 Sprague-Dawley (SD) male rats were randomly divided into 4 groups: ① blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly. CONCLUSIONS: DA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide.


Asunto(s)
Encéfalo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Hipoglucemiantes/farmacología , Incretinas/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Liraglutida/farmacología , Péptidos/farmacología , Daño por Reperfusión/prevención & control , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Ratas Sprague-Dawley , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal , Estreptozocina
14.
J Exp Med ; 218(3)2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33433624

RESUMEN

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.


Asunto(s)
Anticuerpos Bloqueadores/química , Corteza Cerebral , Neuronas , /metabolismo , /antagonistas & inhibidores , Animales , /patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/virología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Neuronas/metabolismo , Neuronas/patología , Neuronas/virología , Organoides/metabolismo , Organoides/patología , Organoides/virología
15.
Cell Stem Cell ; 28(2): 331-342.e5, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33450186

RESUMEN

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.


Asunto(s)
Apolipoproteínas E/metabolismo , Encéfalo/patología , Encéfalo/virología , Células Madre Pluripotentes Inducidas/virología , Tropismo/fisiología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/farmacología , Animales , Antivirales/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/patología , Astrocitos/virología , Diferenciación Celular , Chlorocebus aethiops , Humanos , Degeneración Nerviosa/patología , Neuritas/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/virología , Organoides/efectos de los fármacos , Organoides/patología , Organoides/virología , Isoformas de Proteínas/metabolismo , Sinapsis/patología , Células Vero
16.
Aquat Toxicol ; 231: 105734, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33385846

RESUMEN

Several studies have suggested eugenol as a suitable anaesthetic for fish. However, it has also been regarded as a toxic and aversive substance to several aquatic organisms, including fish. This study sought to assess the eugenol-induced behavioural alterations and its seizurogenic potential to fish. Moreover, a distinctive methodology for an in vivo evaluation of the brain activity was also presented. Prior to the evaluation of eugenol-induced responses, fish were exposed to pentylenetetrazole (PTZ), to characterize any seizure-like patterns. Antagonizing responses to PTZ were assessed in fish receiving diazepam (BDZ) and subsequently exposed to PTZ. Tambaqui fish juveniles, Colossoma macropomum (15.8 ± 2.8 g) were used as models and assayed as follows: (i) fish exposed to PTZ (15 mM) and (ii) fish receiving a dose of BDZ (10 mg Kg-1) and later exposed to PTZ (15 mM) (BDZ-PTZ group). Thereafter, fish were evaluated throughout (iii) eugenol exposure at 65 µL L-1 (ethanolic solution) and recovery. Control fish and a vehicle control group (ethanol at 585 µL L-1) were also established. PTZ baths elicited body immobilization preceded by hyperactivity in a stereotyped seizure-like behaviour with increased EEG wave amplitude and frequency. PTZ effects in the brain were attenuated by a pre-administration of BDZ. Upon eugenol exposure, tambaqui had an intense neuronal excitability, showing a clonus-like seizure behaviour, also corroborated by the EEG patterns, which were consistent with a seizure-like response. Responses of eugenol-exposed fish resembled those of the PZT-exposed animals, with epileptiform discharges. EMG was in line with the EEG modulation, showing increased tracing oscillations and higher mean amplitudes in PTZ-exposed fish whereas in BDZ-PTZ group muscle contraction was less frequent and powerful. Fish exposed to eugenol showed initially some muscle activity followed by a loss of muscle tonus over time. In summary, our results showed that upon eugenol exposure, although a time-dependent body immobilization was attained, fish presented an intense neuronal excitability comparable to that evoked by PTZ. Eugenol failed to promote depression of the CNS and therefore may be not suitable to be used for general anaesthesia of C. macropomum. As eugenol could be implicated in seizurogenesis and be potentially toxic to the fish brain, protocols suggesting the broad use of eugenol for short-term anaesthesia or euthanasia of fish should be carefully revised, as it raises important concerns in terms of ethics and fish welfare.


Asunto(s)
Characiformes/fisiología , Eugenol/toxicidad , Inmovilización , Neuronas/patología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Electrodos , Electroencefalografía , Electromiografía , Fenómenos Electrofisiológicos , Masculino , Músculos/efectos de los fármacos , Neuronas/efectos de los fármacos , Pentilenotetrazol/toxicidad , Contaminantes Químicos del Agua/toxicidad
17.
Nat Neurosci ; 24(3): 355-367, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33495636

RESUMEN

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.


Asunto(s)
Calcio/metabolismo , Corteza Cerebral/metabolismo , Inflamación/metabolismo , Esclerosis Múltiple/metabolismo , Fagocitos/metabolismo , Sinapsis/metabolismo , Animales , Corteza Cerebral/patología , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Modelos Animales de Enfermedad , Sustancia Gris/metabolismo , Sustancia Gris/patología , Inflamación/patología , Ratones , Microglía/metabolismo , Esclerosis Múltiple/patología , Neuronas/metabolismo , Neuronas/patología , Sinapsis/patología
18.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-33445678

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid ß (Aß) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.


Asunto(s)
Envejecimiento/patología , Enfermedad de Alzheimer/patología , Región CA1 Hipocampal/patología , Potenciación a Largo Plazo/fisiología , Red Nerviosa/patología , Neuronas/patología , Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Región CA1 Hipocampal/metabolismo , Cognición/fisiología , Modelos Animales de Enfermedad , Femenino , Interneuronas/metabolismo , Interneuronas/patología , Aprendizaje/fisiología , Masculino , Memoria/fisiología , Ratones , Ratones Transgénicos , Red Nerviosa/metabolismo , Neurregulina-1/metabolismo , Neuronas/metabolismo , Parvalbúminas/metabolismo , Receptor ErbB-4/metabolismo , Transducción de Señal/fisiología , Transmisión Sináptica/fisiología
19.
Nat Commun ; 12(1): 105, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397973

RESUMEN

Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory. Exposure to early life trauma (ELT) has been associated with higher relapse rates in MS patients; however, the underlying mechanisms are not well-defined. Here we show ELT induces mechanistic and phenotypical alterations during experimental autoimmune encephalitis (EAE). ELT sustains downregulation of immune cell adrenergic receptors, which can be attributed to chronic norepinephrine circulation. ELT-subjected mice exhibit interferon-ß resistance and neurodegeneration driven by lymphotoxin and CXCR2 involvement. These phenotypic changes are observed in control EAE mice treated with ß1 adrenergic receptor antagonist. Conversely, ß1 adrenergic receptor agonist treatment to ELT mice abrogates phenotype changes via restoration of immune cell ß1 adrenergic receptor function. Our results indicate that ELT alters EAE phenotype via downregulation of ß1 adrenergic signaling in immune cells. These results have implications for the effect of environmental factors in provoking disease heterogeneity and might enable prediction of long-term outcomes in MS.


Asunto(s)
Regulación hacia Abajo , Interferón beta/metabolismo , Esclerosis Múltiple/complicaciones , Degeneración Nerviosa/complicaciones , Receptores Adrenérgicos beta 1/metabolismo , Transducción de Señal , Estrés Psicológico/complicaciones , Agonistas de Receptores Adrenérgicos beta 1/farmacología , Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Biomarcadores/metabolismo , Encéfalo/inmunología , Encéfalo/patología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/patología , Femenino , Aparato de Golgi/metabolismo , Masculino , Ratones Endogámicos C57BL , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Degeneración Nerviosa/sangre , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/patología , Neuronas/metabolismo , Neuronas/patología , Norepinefrina/sangre , Fenotipo , Índice de Severidad de la Enfermedad , Regulación hacia Arriba/efectos de los fármacos
20.
Nat Commun ; 12(1): 95, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33398028

RESUMEN

Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The transmission of aggregates requires neuron-released Tau to interact with surface receptors on target cells. However, the underlying molecular mechanisms in astrocytes and downstream effects are unclear. Here, using a spatially resolved proteomic mapping strategy, we show that integrin αV/ß1 receptor binds recombinant human Tau, mediating the entry of Tau fibrils in astrocytes. The binding of distinct Tau species to the astrocytic αV/ß1 receptor differentially activate integrin signaling. Furthermore, Tau-mediated activation of integrin signaling results in NFκB activation, causing upregulation of pro-inflammatory cytokines and chemokines, induction of a sub-group of neurotoxic astrocytic markers, and release of neurotoxic factors. Our findings suggest that filamentous recombinant human Tau-mediated activation of integrin signaling induces astrocyte conversion towards a neurotoxic state, providing a mechanistic insight into tauopathies.


Asunto(s)
Astrocitos/metabolismo , Receptores de Vitronectina/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas tau/metabolismo , Animales , Astrocitos/patología , Células Cultivadas , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Células HEK293 , Proteoglicanos de Heparán Sulfato/metabolismo , Humanos , Inflamación/patología , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Neuronas/metabolismo , Neuronas/patología , Unión Proteica , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Talina/metabolismo , Proteínas tau/ultraestructura
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