Browsing by Author "Bronfman C., Francisca"

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    Acetylcholinesterase, a senile plaque component, affects the fibrillogenesis of amyloid-β-peptides
    (1995) Álvarez Rojas, Alejandra; Bronfman C., Francisca; Garrido, Jorge; Inestrosa Cantín, Nibaldo
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    ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity
    (2007) Fuentealba Alday, Rodrigo Esteban; Barría, M. I.; Lee, J.; Cam, J.; Araya, C.; Escudero, C. A.; Inestrosa Cantín, Nibaldo; Bronfman C., Francisca; Bu, G.; Marzolo Canales, María Paz
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    Axonal degeneration induced by glutamate excitotoxicity is mediated by necroptosis
    (2018) Hernández, Diego E.; Salvadores, Natalia A.; Moya Alvarado, Guillermo Adrián; Catalán, Romina J.; Bronfman C., Francisca; Court G., Felipe
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    Axonal PPAR promotes neuronal regeneration after injury
    (2016) Lezana, Juan Pablo; Dagan, Shachar Y.; Robinson, Ari; Goldstein, Ronald S.; Fainzilber, Mike; Bronfman C., Francisca; Bronfman A., Miguel L.
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    Axotomy-induced neurotrophic withdrawal causes the loss of phenotypic differentiation and downregulation of NGF signalling, but not death of septal cholinergic neurons
    (2010) Lazo Jerez, Oscar Marcelo.; Mauna, Jocelyn C.; Pissani Alvear, Claudia.; Inestrosa Cantín, Nibaldo; Bronfman C., Francisca
    Abstract Background Septal cholinergic neurons account for most of the cholinergic innervations of the hippocampus, playing a key role in the regulation of hippocampal synaptic activity. Disruption of the septo-hippocampal pathway by an experimental transection of the fimbria-fornix drastically reduces the target-derived trophic support received by cholinergic septal neurons, mainly nerve growth factor (NGF) from the hippocampus. Axotomy of cholinergic neurons induces a reduction in the number of neurons positive for cholinergic markers in the medial septum. In several studies, the reduction of cholinergic markers has been interpreted as analogous to the neurodegeneration of cholinergic cells, ruling out the possibility that neurons lose their cholinergic phenotype without dying. Understanding the mechanism of cholinergic neurodegeneration after axotomy is relevant, since this paradigm has been extensively explored as an animal model of the cholinergic impairment observed in neuropathologies such as Alzheimer's disease. The principal aim of this study was to evaluate, using modern quantitative confocal microscopy, neurodegenerative changes in septal cholinergic neurons after axotomy and to assess their response to delayed infusion of NGF in rats. Results We found that there is a slow reduction of cholinergic cells labeled by ChAT and p75 after axotomy. However, this phenomenon is not accompanied by neurodegenerative changes or by a decrease in total neuronal number in the medial septum. Although the remaining axotomized-neurons appear healthy, they are unable to respond to delayed NGF infusion. Conclusions Our results demonstrate that at 3 weeks, axotomized cholinergic neurons lose their cholinergic phenotype without dying and down-regulate their NGF-receptors, precluding the possibility of a response to NGF. Therefore, the physiological role of NGF in the adult septal cholinergic system is to support phenotypic differentiation and not survival of neurons. This evidence raises questions about the relationship between transcriptional regulation of the cholinergic phenotype by retrograde-derived trophic signaling and the transcriptional changes experienced when retrograde transport is impaired due to neuropathological conditions.Abstract Background Septal cholinergic neurons account for most of the cholinergic innervations of the hippocampus, playing a key role in the regulation of hippocampal synaptic activity. Disruption of the septo-hippocampal pathway by an experimental transection of the fimbria-fornix drastically reduces the target-derived trophic support received by cholinergic septal neurons, mainly nerve growth factor (NGF) from the hippocampus. Axotomy of cholinergic neurons induces a reduction in the number of neurons positive for cholinergic markers in the medial septum. In several studies, the reduction of cholinergic markers has been interpreted as analogous to the neurodegeneration of cholinergic cells, ruling out the possibility that neurons lose their cholinergic phenotype without dying. Understanding the mechanism of cholinergic neurodegeneration after axotomy is relevant, since this paradigm has been extensively explored as an animal model of the cholinergic impairment observed in neuropathologies such as Alzheimer's disease. The principal aim of this study was to evaluate, using modern quantitative confocal microscopy, neurodegenerative changes in septal cholinergic neurons after axotomy and to assess their response to delayed infusion of NGF in rats. Results We found that there is a slow reduction of cholinergic cells labeled by ChAT and p75 after axotomy. However, this phenomenon is not accompanied by neurodegenerative changes or by a decrease in total neuronal number in the medial septum. Although the remaining axotomized-neurons appear healthy, they are unable to respond to delayed NGF infusion. Conclusions Our results demonstrate that at 3 weeks, axotomized cholinergic neurons lose their cholinergic phenotype without dying and down-regulate their NGF-receptors, precluding the possibility of a response to NGF. Therefore, the physiological role of NGF in the adult septal cholinergic system is to support phenotypic differentiation and not survival of neurons. This evidence raises questions about the relationship between transcriptional regulation of the cholinergic phenotype by retrograde-derived trophic signaling and the transcriptional changes experienced when retrograde transport is impaired due to neuropathological conditions.Abstract Background Septal cholinergic neurons account for most of the cholinergic innervations of the hippocampus, playing a key role in the regulation of hippocampal synaptic activity. Disruption of the septo-hippocampal pathway by an experimental transection of the fimbria-fornix drastically reduces the target-derived trophic support received by cholinergic septal neurons, mainly nerve growth factor (NGF) from the hippocampus. Axotomy of cholinergic neurons induces a reduction in the number of neurons positive for cholinergic markers in the medial septum. In several studies, the reduction of cholinergic markers has been interpreted as analogous to the neurodegeneration of cholinergic cells, ruling out the possibility that neurons lose their cholinergic phenotype without dying. Understanding the mechanism of cholinergic neurodegeneration after axotomy is relevant, since this paradigm has been extensively explored as an animal model of the cholinergic impairment observed in neuropathologies such as Alzheimer's disease. The principal aim of this study was to evaluate, using modern quantitative confocal microscopy, neurodegenerative changes in septal cholinergic neurons after axotomy and to assess their response to delayed infusion of NGF in rats. Results We found that there is a slow reduction of cholinergic cells labeled by ChAT and p75 after axotomy. However, this phenomenon is not accompanied by neurodegenerative changes or by a decrease in total neuronal number in the medial septum. Although the remaining axotomized-neurons appear healthy, they are unable to respond to delayed NGF infusion. Conclusions Our results demonstrate that at 3 weeks, axotomized cholinergic neurons lose their cholinergic phenotype without dying and down-regulate their NGF-receptors, precluding the possibility of a response to NGF. Therefore, the physiological role of NGF in the adult septal cholinergic system is to support phenotypic differentiation and not survival of neurons. This evidence raises questions about the relationship between transcriptional regulation of the cholinergic phenotype by retrograde-derived trophic signaling and the transcriptional changes experienced when retrograde transport is impaired due to neuropathological conditions.
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    BDNF Regulates Rab11-Mediated Recycling Endosome Dynamics to Induce Dendritic Branching
    (2013) Lazo Jerez, Oscar Marcelo.; Bronfman C., Francisca
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    Brain-Derived Neurotrophic Factor (BDNF) Regulates Rab5-Positive Early Endosomes in Hippocampal Neurons to Induce Dendritic Branching
    (2018) Moya-Alvarado, Guillermo; Gonzalez, Andres; Stuardo, Nicolas; Bronfman C., Francisca
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    Cellular and molecular mechanisms regulating neuronal growth by brain-derived neurotrophic factor
    (2016) González, A.; Moya Alvarado, Guillermo Adrián; González Billaut, C.; Bronfman C., Francisca
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    Cholinergic abnormalities, endosomal alterations and up-regulation of nerve growth factor signaling in Niemann-Pick Type C disease
    (2012) Cabeza Huerta, Carolina Andrea; Figueroa, Alicia; Lazo Jerez, Oscar Marcelo; Galleguillos, Carolina; Pissani Alvear, Claudia; Klein, Andrés; Inestrosa Cantín, Nibaldo; Álvarez Rojas, Alejandra; Zanlungo Matsuhiro, Silvana; Bronfman C., Francisca; Gonzalez-Billault, Christian
    Abstract Background Neurotrophins and their receptors regulate several aspects of the developing and mature nervous system, including neuronal morphology and survival. Neurotrophin receptors are active in signaling endosomes, which are organelles that propagate neurotrophin signaling along neuronal processes. Defects in the Npc1 gene are associated with the accumulation of cholesterol and lipids in late endosomes and lysosomes, leading to neurodegeneration and Niemann-Pick type C (NPC) disease. The aim of this work was to assess whether the endosomal and lysosomal alterations observed in NPC disease disrupt neurotrophin signaling. As models, we used i) NPC1-deficient mice to evaluate the central cholinergic septo-hippocampal pathway and its response to nerve growth factor (NGF) after axotomy and ii) PC12 cells treated with U18666A, a pharmacological cellular model of NPC, stimulated with NGF. Results NPC1-deficient cholinergic cells respond to NGF after axotomy and exhibit increased levels of choline acetyl transferase (ChAT), whose gene is under the control of NGF signaling, compared to wild type cholinergic neurons. This finding was correlated with increased ChAT and phosphorylated Akt in basal forebrain homogenates. In addition, we found that cholinergic neurons from NPC1-deficient mice had disrupted neuronal morphology, suggesting early signs of neurodegeneration. Consistently, PC12 cells treated with U18666A presented a clear NPC cellular phenotype with a prominent endocytic dysfunction that includes an increased size of TrkA-containing endosomes and reduced recycling of the receptor. This result correlates with increased sensitivity to NGF, and, in particular, with up-regulation of the Akt and PLC-γ signaling pathways, increased neurite extension, increased phosphorylation of tau protein and cell death when PC12 cells are differentiated and treated with U18666A. Conclusions Our results suggest that the NPC cellular phenotype causes neuronal dysfunction through the abnormal up-regulation of survival pathways, which causes the perturbation of signaling cascades and anomalous phosphorylation of the cytoskeleton.
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    Endosomal transport of neurotrophins: roles in signaling and neurodegenerative diseases
    (2007) Bronfman C., Francisca; Escudero Izquierdo, Claudia Andrea.
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    Laminin Blocks the Assembly of Wild-Type Ab and the Dutch Variant Peptide Into Alzheimer's Figrils
    (1998) Bronfman C., Francisca; Inestrosa Cantín, Nibaldo
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    Laminin Inhibits Amyloid-B-Peptide Fibrillation
    (1996) Bronfman C., Francisca; Garrido, Jorge; Álvarez Rojas, Alejandra; Inestrosa Cantín, Nibaldo
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    Mechanisms of long-distance control of dendritic growth by Brain-Derived Neurotrophic Factor (BDNF) in central neurons.
    (2019) Moya Alvarado, Guillermo Adrián; Bronfman C., Francisca; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    El factor neurotrófico derivado del cerebro (BDNF) se expresa ampliamente en muchos circuitos del sistema nervioso central (SNC) y se une a sus receptores TrkB y p75 para desencadenar diferentes vías de señalización, tales como las quinasas ERK1/2, PI3K-mTOR y la vía de la PLCg-Ca+2. De esta manera favorece el crecimiento dendrítico y la plasticidad sináptica. Una vez que BDNF une a sus receptores de membrana TrkB y p75, estos se endocitan formando endosomas de señalización. En el sistema nervioso periférico (SNP) está descrito que las neurotrofinas unen a sus receptores en el axón y transmiten señales al cuerpo celular mediante el transporte axonal de endosomas de señalización favoreciendo la sobrevida neuronal. Sin embargo, el rol funcional de los endosomas de señalización BDNF/TrkB en las neuronas centrales, se desconoce. El propósito general de esta tesis fue estudiar el papel de la ruta endosomal en la señalización a larga distancia de BDNF/TrkB en las neuronas corticales y su regulación por las vías clásicas de regulación como PI3K y PLCg. El primer objetivo de nuestro trabajo fue estudiar si BDNF aumenta la actividad de la GTPasa Rab5 de manera temporal y espacial y si esto se traduce en una modificación de la dinámica de estos endosomas en dendritas y cuerpos celulares. Las proteínas Rabs son GTPasas monoméricas que actúan como interruptores moleculares para regular el tráfico de membranas al unirse a una amplia gama de efectores. Entre las Rab GTPasas, Rab5 es la GTPasa clave que regula los endosomas tempranos y es el primer organelo en la ruta endocítica de receptores de membrana. Para estudiar el rol de Rab5 sobre la señalización neuronal de BDNF, nosotros hicimos experimentos de microscopía de fluorescencia en células fijadas y células vivas, además evaluamos, mediante el uso de adenovirus que sobreexpresan un dominante negativo de Rab5, si la actividad de la GTPasa era requerida para la arborización inducida por BDNF. Nuestros estudios mostraron que tiempos breves de tratamiento con BDNF aumentó la colocalización de TrkB con Rab5 en dendritas, aumentando el número y la movilidad de los endosomas positivos para Rab5. Estos hallazgos se complementan con estudios que mostraron que la actividad de Rab5 es requerida para la ramificación dendrítica inducida por BDNF. Estos datos muestran que BDNF regula la dinámica de los endosomas tempranos mediante el aumento de la actividad y número de endosomas Rab5 y sugieren que estos procesos son requeridos para la ramificación dendrítica inducida por BDNF. Posteriormente, nos preguntamos por el rol funcional de la señalización axonal de BDNF en las neuronas corticales y el posible papel de los endosomas de señalización. Para esto utilizamos cultivos de neuronas corticales sembradas en cámaras de microfluidos, modelo que nos permitió aislar el componente axonal del somatodendrítico y así estudiar mediante microscopía de fluorescencia el efecto de la estimulación axonal de BDNF sobre la ruta de señalización de TrkB en los cuerpos celulares y axones. Nosotros encontramos que la incubación con BDNF en axones aumenta la ramificación dendrítica en los cuerpos celulares. Usando distintos modelos de animales transgénicos, encontramos que este proceso es mayormente mediado por los receptores TrkB y no p75. Además, encontramos que la arborización dependía de la activación del factor de transcripción CREB en el núcleo y la vía PI3K-mTOR en los cuerpos celulares aumentando la síntesis de proteínas somatodendríticas. Por otra parte, la actividad de PI3K en axones no fue necesaria para el transporte de BDNF, ni para el efecto en la arborización en el cuerpo celular. Mediante el uso de neuronas corticales derivadas de ratones knock-in TrkBF616A y el uso de cultivos compartimentalizados, pudimos mostrar que se requiere de la actividad del receptor TrkB activo en el cuerpo celular inducido por BDNF en el axón, para los efectos dendríticos observados en el cuerpo celular. Por otro lado, las actividades de Rab5 y dineína fueron requeridas para estos efectos. Todos estos resultados en su conjunto sugieren la generación y transporte de endosomas de señalización para la señalización a larga distancia de BDNF. A continuación, debido a la poca información disponible sobre cómo las rutas rio abajo de TrkB regulan la señalización de larga distancia, estudiamos el papel de la señalización de la PLCg en la señalización axonal mediada por BDNF. Utilizando cultivos compartimentalizados, demostramos que la actividad axonal de PLCg es necesaria para la arborización dendrítica y la fosforilación de CREB. Estos resultados se correlacionaron con el aumento de los niveles axonales de Ca+2 inducido por BDNF en los axones de una manera dependiente del PLCg. Adicionalmente, encontramos que la ruta PLCg/Ca+2 es necesaria para la endocitosis de TrkB en el axón. En resumen, estos resultados sugieren que la señalización axonal a larga distancia de BDNF posee un rol funcional en neuronas corticales, regulando la activación de proteínas claves para la traducción de proteínas y la arborización dendrítica.