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1.
Cell Syst ; 15(5): 425-444.e9, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38703772

RESUMEN

The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications-Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.


Asunto(s)
Placenta , Análisis de la Célula Individual , Humanos , Femenino , Embarazo , Placenta/microbiología , Placenta/inmunología , Análisis de la Célula Individual/métodos , Plasmodium falciparum , Listeria monocytogenes/patogenicidad , Listeria monocytogenes/fisiología , Toxoplasma/patogenicidad , Macrófagos/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Toxoplasmosis/inmunología , Toxoplasmosis/metabolismo , Inflamación
2.
Metallomics ; 16(1)2024 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-38178638

RESUMEN

Demyelination within the central nervous system (CNS) is a significant feature of debilitating neurological diseases such as multiple sclerosis and administering the copper-selective chelatorcuprizone to mice is widely used to model demyelination in vivo. Conspicuous demyelination within the corpus callosum is generally attributed to cuprizone's ability to restrict copper availability in this vulnerable brain region. However, the small number of studies that have assessed copper in brain tissue from cuprizone-treated mice have produced seemingly conflicting outcomes, leaving the role of CNS copper availability in demyelination unresolved. Herein we describe our assessment of copper concentrations in brain samples from mice treated with cuprizone for 40 d. Importantly, we applied an inductively coupled plasma mass spectrometry methodology that enabled assessment of copper partitioned into soluble and insoluble fractions within distinct brain regions, including the corpus callosum. Our results show that cuprizone-induced demyelination in the corpus callosum was associated with decreased soluble copper in this brain region. Insoluble copper in the corpus callosum was unaffected, as were pools of soluble and insoluble copper in other brain regions. Treatment with the blood-brain barrier permeant copper compound CuII(atsm) increased brain copper levels and this was most pronounced in the soluble fraction of the corpus callosum. This effect was associated with significant mitigation of cuprizone-induced demyelination. These results provide support for the involvement of decreased CNS copper availability in demyelination in the cuprizone model. Relevance to human demyelinating disease is discussed.


Asunto(s)
Cuprizona , Enfermedades Desmielinizantes , Humanos , Animales , Ratones , Cuprizona/efectos adversos , Cuerpo Calloso , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Cobre/farmacología , Oligodendroglía , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Vaina de Mielina
3.
J Environ Manage ; 345: 118449, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37390731

RESUMEN

Mechanical separation of anaerobic digestate has been identified as a method to reduce pollution risk to waterways by partitioning phosphorus in the solid fraction and reducing its application to land. Separators have adjustable parameters which affect separation efficiency, and hence the degree of phosphorous partitioning, but information on how these parameters affect separation performance is limited in the literature. Two well known technologies were investigated, decanter centrifuge and screw press, to determine the most efficient method of separation. Counterweight load and the use of an oscillator were adjusted for the screw press, while bowl speed, auger differential speed, feed rate and polymer addition were modified for the decanter centrifuge. Separation efficiency was determined for total solids, phosphorus, nitrogen, potassium, and carbon, and the total solids content of resulting fractions was measured. The decanter centrifuge had higher separation efficiency for phosphorus in all cases, ranging from 51% to 71.5%, while the screw press had a phosphorus separation efficiency ranging from 8.5% to 10.9% for digestate of ∼5% solids (slurry/grass silage mix). Separation by decanter centrifuge partitioned up to 56% of nitrogen in the solid fraction leaving a reduced nitrogen content in the liquid fraction available for land spreading; this nitrogen would most likely need to be replaced by chemical fertiliser which would add to the cost of the system. The decanter centrifuge is better suited to cases where phosphorus recovery is the most important factor, while the screw press could be advantageous in cases where cost is a limiting factor.


Asunto(s)
Contaminación Ambiental , Nitrógeno , Anaerobiosis , Nitrógeno/análisis , Estiércol , Fósforo/química
4.
Glia ; 71(4): 1120-1141, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36583573

RESUMEN

The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2ΔO/ΔO ). At 6 weeks of age, normal-appearing myelin had formed in CerS2ΔO/ΔO mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2ΔO/ΔO mice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2ΔO/ΔO mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2ΔO/ΔO mice. By 16 weeks, CerS2ΔO/ΔO mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2ΔO/ΔO mice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases.


Asunto(s)
Microglía , Vaina de Mielina , Ratones , Animales , Microglía/metabolismo , Vaina de Mielina/metabolismo , Ceramidas/metabolismo , Esfingolípidos/metabolismo
5.
Shoulder Elbow ; 14(6): 642-647, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36479011

RESUMEN

Midshaft clavicle fractures are commonly fixed with locking plates. The subclavian vein risks injury during this procedure and the consequences can be fatal. The purpose of this present study is to describe a clavicular osteotomy technique in order to equip orthopaedic surgeons with a means of rapidly accessing a subclavian vein injury. The osteotomy should only be performed following an urgent intraoperative vascular surgery assessment. There must be shared consensus from both orthopaedic and vascular surgery that direct repair of the subclavian vein is necessary, and further exposure is required. The results of the technique performed on thirteen embalmed cadaveric specimens are also included. The osteotomy was able to expose 3.16 cm (SD = 0.60) of the subclavian vein and both the fracture and osteotomy site of all clavicles (100%) were able to be reduced and fixed using a single pre-contoured fifteen-hole lateral plate intended for use on the contralateral shoulder. This surgical technique study confirms that in the rare circumstance that the osteotomy is utilized, adequate exposure of the subclavian vein is achieved.

6.
Eur J Neurosci ; 56(12): 6099-6114, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36217300

RESUMEN

Oligodendrocyte production and myelination continues lifelong in the central nervous system (CNS), and all stages of this process can be adaptively regulated by neuronal activity. While artificial exogenous stimulation of neuronal circuits greatly enhances oligodendrocyte progenitor cell (OPC) production and increases myelination during development, the extent to which physiological stimuli replicates this is unclear, particularly in the adult CNS when the rate of new myelin addition slows. Here, we used environmental enrichment (EE) to physiologically stimulate neuronal activity for 6 weeks in 9-week-old C57BL/six male and female mice and found no increase in compact myelin in the corpus callosum or somatosensory cortex. Instead, we observed a global increase in callosal axon diameter with thicker myelin sheaths, elongated paranodes and shortened nodes of Ranvier. These findings indicate that EE induced the dynamic structural remodelling of myelinated axons. Additionally, we observed a global increase in the differentiation of OPCs and pre-myelinating oligodendroglia in the corpus callosum and somatosensory cortex. Our findings of structural remodelling of myelinated axons in response to physiological neural stimuli during young adulthood provide important insights in understanding experience-dependent myelin plasticity throughout the lifespan and provide a platform to investigate axon-myelin interactions in a physiologically relevant context.


Asunto(s)
Axones , Vaina de Mielina , Animales , Masculino , Femenino , Ratones , Ratones Endogámicos C57BL , Axones/fisiología , Oligodendroglía/fisiología , Encéfalo , Diferenciación Celular/fisiología
7.
J Craniofac Surg ; 33(7): 2178-2180, 2022 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-36201704

RESUMEN

BACKGROUND: The implications on the choice of donor side when using the free fibula flap for reconstruction of unilateral maxillectomy defects has not been discussed in the literature so far. METHODS: A unilateral maxillectomy reconstruction was replicated using a 3D-printed skull model and fresh cadaveric dissections of left and right osteomyocutaneous fibula flaps for comparison. Detailed photo documentation was conducted to analyze and illustrate the anatomical differences of performing a reconstruction using the ipsilateral or contralateral sides and their relative benefits and risks. RESULTS: A more favorable lie of the septum and skin paddle and flexor hallucis longus muscle is attainable depending on which donor side is used and the planned direction of the pedicle. CONCLUSION: This study demonstrates why it is preferable to use the ipsilateral fibula if anastomosis is to the ipsilateral facial or neck recipient vessels, or the contralateral fibula where the contralateral recipient vessels are preferred.


Asunto(s)
Colgajos Tisulares Libres , Procedimientos de Cirugía Plástica , Peroné/trasplante , Colgajos Tisulares Libres/cirugía , Humanos , Maxilar/cirugía
9.
Exp Neurol ; 339: 113652, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33609501

RESUMEN

Young children have a high risk of sustaining a traumatic brain injury (TBI), which can have debilitating life-long consequences. Importantly, the young brain shows particular vulnerability to injury, likely attributed to ongoing maturation of the myelinating nervous system at the time of insult. Here, we examined the effect of acute treatment with the partial tropomyosin receptor kinase B (TrkB) agonist, LM22A-4, on pathological and neurobehavioral outcomes after pediatric TBI, with the hypothesis that targeting TrkB would minimize tissue damage and support functional recovery. We focused on myelinated tracts-the corpus callosum and external capsules-based on recent evidence that TrkB activation potentiates oligodendrocyte remyelination. Male mice at postnatal day 21 received an experimental TBI or sham surgery. Acutely post-injury, extensive cell death, a robust glial response and disruption of compact myelin were evident in the injured brain. TBI or sham mice then received intranasal saline vehicle or LM22A-4 for 14 days. Behavior testing was performed from 4 weeks post-injury, and brains were collected at 5 weeks for histology. TBI mice showed hyperactivity, reduced anxiety-like behavior, and social memory impairments. LM22A-4 ameliorated the abnormal anxiolytic phenotype but had no effect on social memory deficits. Use of spectral confocal reflectance microscopy detected persistent myelin fragmentation in the external capsule of TBI mice at 5 weeks post-injury, which was accompanied by regionally distinct deficits in oligodendrocyte progenitor cells and post-mitotic oligodendrocytes, as well as chronic reactive gliosis and atrophy of the corpus callosum and injured external capsule. LM22A-4 treatment ameliorated myelin deficits in the perilesional external capsule, as well as tissue volume loss and the extent of reactive gliosis. However, there was no effect of this TrkB agonist on oligodendroglial populations detected at 5 weeks post-injury. Collectively, our results demonstrate that targeting TrkB immediately after TBI during early life confers neuroprotection and preserves myelin integrity, and this was associated with some improved neurobehavioral outcomes as the pediatric injured brain matures.


Asunto(s)
Benzamidas/administración & dosificación , Lesiones Traumáticas del Encéfalo/prevención & control , Glicoproteínas de Membrana/agonistas , Vaina de Mielina/efectos de los fármacos , Neuroprotección/efectos de los fármacos , Remielinización/efectos de los fármacos , Animales , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Modelos Animales de Enfermedad , Esquema de Medicación , Masculino , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Neuroprotección/fisiología , Proteínas Tirosina Quinasas , Remielinización/fisiología , Resultado del Tratamiento
10.
Glia ; 68(12): 2725-2743, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32658363

RESUMEN

Diabetic neuropathy has an incidence as high as 50% of diabetic patients and is characterized by damage to neurons, Schwann cells and blood vessels within the peripheral nervous system. The low-affinity neurotrophin receptor p75 (p75NTR ), particularly expressed by the Schwann cells in the peripheral nerve, has previously been reported to play a role in developmental myelination and cell survival/death. Increased levels of p75NTR , in the endoneurium and plasma from diabetic patients and rodent models of disease, have been observed, proposing that this receptor might be involved in the pathogenesis of diabetic neuropathy. Therefore, in this study, we addressed this hypothesis by utilizing a mouse model of selective nerve growth factor receptor (Ngfr) deletion in Schwann cells (SC-p75NTR -KO). Electron microscopy of sciatic nerves from mice with high fat diet induced obesity demonstrated how loss of Schwann cell-p75NTR aggravated axonal atrophy and loss of C-fibers. RNA sequencing disclosed several pre-clinical signaling alterations in the diabetic peripheral nerves, dependent on Schwann cell p75NTR signaling, specially related with lysosome, phagosome, and immune pathways. Morphological and biochemical analyses identified abundant lysosomes and autophagosomes in the C-fiber axoplasm of the diabetic SC-p75NTR -KO nerves, which together with increased Cathepsin B protein levels corroborates gene upregulation from the phagolysosomal pathways. Altogether, this study demonstrates that Schwann cell p75NTR deficiency amplifies diabetic neuropathy disease by triggering overactivation of immune-related pathways and increased lysosomal stress.


Asunto(s)
Neuropatías Diabéticas , Células de Schwann , Animales , Axones , Humanos , Ratones , Receptor de Factor de Crecimiento Nervioso , Receptores de Factor de Crecimiento Nervioso/genética , Nervio Ciático
11.
J Neurosci Res ; 98(10): 1987-1998, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32585763

RESUMEN

The p75 neurotrophin receptor (p75NTR ) is required for maintaining peripheral sensory neuron survival and function; however, the underlying cellular mechanism remains unclear. The general view is that expression of p75NTR by the neuron itself is required for maintaining sensory neuron survival and myelination in the peripheral nervous system (PNS). Adopting a neuronal-specific conditional knockout strategy, we demonstrate the partial depletion of p75NTR in neurons exerts little influence upon maintaining sensory neuron survival and peripheral nerve myelination in health and after demyelinating neuropathy. Our data show that the density and total number of dorsal root ganglion (DRG) neurons in 2-month-old mice is not affected following the deletion of p75NTR in large-diameter myelinating neurons, as assessed by stereology. Adopting experimental autoimmune neuritis induced in adult male mice, an animal model of demyelinating peripheral neuropathy, we identify that deleting p75NTR in myelinating neurons exerts no influence upon the disease progression, the total number of DRG neurons, and the extent of myelin damage in the sciatic nerve, indicating that the expression of neuronal p75NTR is not essential for maintaining peripheral neuron survival and myelination after a demyelinating insult in vivo. Together, results of this study suggest that the survival and myelination of peripheral sensory neurons is independent of p75NTR expressed by a subtype of neurons in vivo. Thus, our findings provide new insights into the mechanism underpinning p75NTR -mediated neuronal survival in the PNS.


Asunto(s)
Ganglios Espinales/metabolismo , Receptores de Factor de Crecimiento Nervioso/deficiencia , Receptores de Factor de Crecimiento Nervioso/genética , Células Receptoras Sensoriales/metabolismo , Animales , Supervivencia Celular/fisiología , Femenino , Eliminación de Gen , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos
12.
Front Mol Neurosci ; 12: 275, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31803018

RESUMEN

Developing a high-throughput approach to quantify the extent of myelin integrity in preclinical models of demyelinating diseases will enhance our capacity to identify novel therapies for myelin repair. In light of the technical limitations of electron microscopy and immunohistochemical analyses of myelination, we have utilized a novel imaging technique, spectral confocal reflectance (SCoRe) microscopy. SCoRe takes advantage of the optically reflective properties of compact myelin, allowing the integrity of compact myelin to be quantified over the course of the cuprizone-induced model of central demyelination. We applied SCoRe imaging on fixed frozen brain sections. SCoRe analysis of control mice identified an increase in corpus callosum myelination during the period of cuprizone administration and recovery, suggesting that the normal developmental processes of myelination are ongoing at this time. Importantly, analysis of mice subjected to cuprizone identified a significant reduction in compact myelin in both rostral and caudal corpus callosum compared to age-matched control mice. SCoRe microscopy also allowed the visualization and quantification of the amount of myelin debris in demyelinating lesions. Combining SCoRe imaging with immunohistochemistry, we quantified the amount of myelin debris within IBA-1+ microglia and found that 11% of myelin debris colocalized in microglia irrespective of the callosal regions, with the vast majority of debris outside of microglia. In summary, we have demonstrated that SCoRe microscopy is an effective and powerful tool to perform both quantitative and qualitative analyses of compact myelin integrity in health or after injury in vivo, demonstrating its future application in high-throughput assessments and screening of the therapeutic efficacy of myelin repair therapies in preclinical animal models of demyelinating diseases.

13.
Front Mol Neurosci ; 12: 205, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31507374

RESUMEN

The neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in a cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after 1-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.

14.
Front Cell Neurosci ; 13: 235, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31191256

RESUMEN

Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75NTR has been identified as a positive modulator for Schwann cell myelination during development and implicated in promoting nerve regeneration after injury. However, most studies base this conclusion on results obtained from complete p75NTR knockout mouse models and cannot dissect the specific role of p75NTR expressed by Schwann cells. In this present study, a conditional knockout model selectively deleting p75NTR expression in Schwann cells was generated, where p75NTR expression is replaced with that of an mCherry reporter. Silencing of Schwann cell p75NTR expression was confirmed in the sciatic nerve in vivo and in vitro, without altering axonal expression of p75NTR. No difference in sciatic nerve myelination during development or following sciatic nerve crush injury was observed, as determined by quantification of both myelinated and unmyelinated nerve fiber densities, myelinated axonal diameter and myelin thickness. However, the absence of Schwann cell p75NTR reduced motor nerve conduction velocity after crush injury. Our data indicate that the absence of Schwann cell p75NTR expression in vivo is not critical for axonal regrowth or remyelination following sciatic nerve crush injury, but does play a key role in functional recovery. Overall, this represents the first step in redefining the role of p75NTR in the peripheral nervous system, suggesting that the Schwann cell-axon unit functions as a syncytium, with the previous published involvement of p75NTR in remyelination most likely depending on axonal/neuronal p75NTR and/or mutual glial-axonal interactions.

15.
Behav Brain Res ; 372: 111984, 2019 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-31150746

RESUMEN

Schizophrenia is a debilitating disorder characterised by three main symptom categories: positive, negative and cognitive. Cognitive symptoms emerge first, and currently do not have appropriate treatments, despite being a strong predictor of the severity and progress of the illness. Cognitive deficits are strongly associated with the dysfunction of GABAergic parvalbumin interneurons (PV-IN). PV-IN are supported by Brain-Derived Neurotrophic Factor (BDNF) via its receptor Tropomyosin-related Kinase B (TrkB). The main aim of this study was to investigate the cognitive and affective consequences of disrupted BDNF-TrkB signalling at PV-IN. We crossed PV-Cre mice with heterozygous TrkB floxed mice (PV-Cre:Fl+/-) to knock-down TrkB receptors on PV-IN. Male and female mice underwent a battery of tests including: Y-Maze, Cheeseboard Maze, Elevated Plus Maze, and Locomotor activity. Co-expression of PV and TrkB in the hippocampus was assessed by fluorescent immunohistochemistry and detailed stereology. Sex-specific spatial memory impairments were found in the Y-Maze. Only male PV-Cre:Fl+/- mice showed no preference for the novel arm. Furthermore, there was a male specific genotype difference in memory retrieval in the Cheeseboard Maze. Male PV-Cre:Fl+/- mice were more preservative in their learning than male PV-Cre control mice. Overall, the evidence from this study suggests that sex had a developmental influence on this constitutive model. Male spatial memory was altered by the disruption to BDNF-TrkB signalling at PV-IN. This aligns with males showing more severe cognitive dysfunction in schizophrenia.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Interneuronas/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Memoria Espacial/fisiología , Animales , Conducta Animal/fisiología , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/fisiología , Cognición/fisiología , Femenino , Neuronas GABAérgicas/metabolismo , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria , Ratones , Ratones Endogámicos C57BL , Parvalbúminas/metabolismo , Transducción de Señal/fisiología
16.
eNeuro ; 6(2)2019.
Artículo en Inglés | MEDLINE | ID: mdl-31028086

RESUMEN

Blocking inhibitory factors within CNS demyelinating lesions is regarded as a promising strategy to promote remyelination. Bone morphogenetic protein 4 (BMP4) is an inhibitory factor present in demyelinating lesions. Noggin, an endogenous antagonist to BMP, has previously been shown to increase the number of oligodendrocytes and promote remyelination in vivo. However, it remains unclear how BMP4 signaling inhibits remyelination. Here we investigated the downstream signaling pathway that mediates the inhibitory effect that BMP4 exerts upon remyelination through pharmacological and transgenic approaches. Using the cuprizone mouse model of central demyelination, we demonstrate that selectively blocking BMP4 signaling via the pharmacological inhibitor LDN-193189 significantly promotes oligodendroglial differentiation and the extent of remyelination in vivo This was accompanied by the downregulation of transcriptional targets that suppress oligodendrocyte differentiation. Further, selective deletion of BMP receptor type IA (BMPRIA) within primary mouse oligodendrocyte progenitor cells (OPCs) significantly enhanced their differentiation and subsequent myelination in vitro Together, the results of this study identify that BMP4 signals via BMPRIA within OPCs to inhibit oligodendroglial differentiation and their capacity to myelinate axons, and suggest that blocking the BMP4/BMPRIA pathway in OPCs is a promising strategy to promote CNS remyelination.


Asunto(s)
Proteína Morfogenética Ósea 4/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Enfermedades Desmielinizantes/metabolismo , Células-Madre Neurales/metabolismo , Oligodendroglía/metabolismo , Remielinización , Transducción de Señal , Animales , Proteína Morfogenética Ósea 4/antagonistas & inhibidores , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/deficiencia , Diferenciación Celular/efectos de los fármacos , Enfermedades Desmielinizantes/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células-Madre Neurales/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Remielinización/efectos de los fármacos
17.
Mol Neurobiol ; 56(2): 1262-1275, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29881947

RESUMEN

Brain-derived neurotrophic factor (BDNF) is highly expressed in the hippocampus, where it can initiate signalling pathways leading to neurite outgrowth, neuron survival, spine maturation and increased synapse strength. Although suppressor of cytokine signalling 2 (SOCS2) is primarily known to negatively regulate cytokine signalling, it is also highly expressed in the hippocampus and exerts neuron-specific functions in the brain, effecting the length and architecture of neurons. However, little is known about the role of SOCS2 in the hippocampus. In this study, we hypothesised that SOCS2 may have a regulatory role in BDNF-dependent neurite growth and hippocampal neuronal function. Here our data demonstrate that SOCS2 interacts with the kinase domain of the BDNF receptor TrkB. Germline overexpression of SOCS2 results in a BDNF-dependent increase in hippocampal neurite outgrowth, whereas deletion of SOCS2 results in shorter neurite outgrowth. Expression of SOCS2 also results in increased ubiquitination of the juxtamembrane region of TrkB, and alters the trafficking of TrkB into recycling endosomes. Collectively, our data suggest a novel role for SOCS2 in interacting with and regulating the trafficking of TrkB, leading to increased neurite outgrowth in hippocampus neurons.


Asunto(s)
Hipocampo/metabolismo , Glicoproteínas de Membrana/metabolismo , Neuritas/metabolismo , Proyección Neuronal/fisiología , Neuronas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Células HEK293 , Hipocampo/efectos de los fármacos , Humanos , Glicoproteínas de Membrana/genética , Ratones , Neuritas/efectos de los fármacos , Proyección Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Fosforilación , Proteínas Tirosina Quinasas/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Proteínas Supresoras de la Señalización de Citocinas/genética
18.
Int J Mol Sci ; 19(12)2018 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-30572673

RESUMEN

Brain-derived neurotrophic factor (BDNF) plays vitally important roles in neural development and plasticity in both health and disease. Recent studies using mutant mice to selectively manipulate BDNF signalling in desired cell types, in combination with animal models of demyelinating disease, have demonstrated that BDNF not only potentiates normal central nervous system myelination in development but enhances recovery after myelin injury. However, the precise mechanisms by which BDNF enhances myelination in development and repair are unclear. Here, we review some of the recent progress made in understanding the influence BDNF exerts upon the myelinating process during development and after injury, and discuss the cellular and molecular mechanisms underlying its effects. In doing so, we raise new questions for future research.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Vaina de Mielina/metabolismo , Regeneración Nerviosa , Plasticidad Neuronal , Animales , Humanos , Receptor trkB/metabolismo
19.
J Neurosci ; 38(32): 7088-7099, 2018 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-29976621

RESUMEN

Methods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. In female mice, we show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons, and myelin sheath thickness after a demyelinating insult. Treatment with exogenous BDNF exerted an attenuated effect, increasing myelin sheath thickness only. Further, following conditional deletion of TrkB from premyelinating oligodendrocytes, we show the effects of the BDNF-mimetic on oligodendrocyte differentiation and remyelination are lost, indicating these are dependent on oligodendrocyte expression of TrkB. Overall, these studies demonstrate that targeting oligodendrocyte TrkB promotes in vivo remyelination in the brain.SIGNIFICANCE STATEMENT Novel strategies to promote myelin regeneration are required to prevent progressive neurodegeneration and clinical disability in patients with central demyelinating disease. Here, we test whether selectively targeting the TrkB receptor on the myelin-producing oligodendrocytes, can promote remyelination in the brain. Using a structural mimetic of its native ligand, BDNF, we show that stimulation of TrkB enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons and thickness of the myelin sheath following a demyelinating insult. Further, we show that these effects are dependent on the phosphorylation of oligodendrocyte expressed TrkB receptors in vivo Overall, we demonstrate that selective targeting of TrkB has therapeutic potential to promote remyelination in the brain.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/uso terapéutico , Encéfalo/efectos de los fármacos , Enfermedades Desmielinizantes/tratamiento farmacológico , Glicoproteínas de Membrana/agonistas , Terapia Molecular Dirigida , Vaina de Mielina/metabolismo , Oligodendroglía/efectos de los fármacos , Remielinización/efectos de los fármacos , Animales , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/farmacología , División Celular/efectos de los fármacos , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Cuprizona/toxicidad , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Femenino , Bombas de Infusión Implantables , Infusiones Intraventriculares , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Básica de Mielina/biosíntesis , Células-Madre Neurales/efectos de los fármacos , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Fosforilación , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Tirosina Quinasas/metabolismo , Organismos Libres de Patógenos Específicos
20.
Methods Mol Biol ; 1791: 243-250, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30006715

RESUMEN

Mouse models of peripheral demyelinating neuropathy play an important role in enabling the study of disease pathogenesis. Further, induction in transgenic mice allows for the precise interrogation of disease mechanisms, as well as the analysis of the efficacy and mechanisms of potential new therapies. Here we describe a method to successfully induce experimental autoimmune neuritis (EAN) using myelin protein zero (P0)180-199 peptide in combination with Freund's complete adjuvant and pertussis toxin in the C57BL/6 mouse strain. We also outline a sensitive paradigm of accurately assessing the extent of functional deficits occurring in murine EAN.


Asunto(s)
Proteína P0 de la Mielina/inmunología , Neuritis Autoinmune Experimental/inmunología , Fragmentos de Péptidos/inmunología , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Marcha , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Proteína P0 de la Mielina/química , Proteína P0 de la Mielina/metabolismo , Neuritis Autoinmune Experimental/diagnóstico , Neuritis Autoinmune Experimental/metabolismo , Neuritis Autoinmune Experimental/fisiopatología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Toxina del Pertussis/administración & dosificación , Toxina del Pertussis/efectos adversos , Toxina del Pertussis/inmunología
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