Browsing by Author "Álvarez Rojas, Alejandra"

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    A Cdk5–p35 Stable Complex Is Involved in the β-Amyloid-Induced Deregulation of Cdk5 Activity in Hippocampal Neurons
    (2001) Álvarez Rojas, Alejandra; Muñoz, Juan Pablo; Maccioni, Ricardo B.
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    Acetylcholinesterase Accelerates Assembly of Amyloid-β-Peptides Into Alzheimer's Fibrils: Possible Role of the Peripheral Site of the Enzyme
    (1996) Inestrosa Cantín, Nibaldo; Álvarez Rojas, Alejandra; Moreno Mauro, Ricardo D.; Garrido, Jorge
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    Acetylcholinesterase promotes the aggregation of amyloid-β-peptide fragments by forming a complex with the growing fibrils
    (1997) Álvarez Rojas, Alejandra; Garrido, Jorge; Inestrosa Cantín, Nibaldo
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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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    Acetylcholinesterase-Amyloid-β-Peptide Interaction: Effect of Congo Red and the Roles of the Wnt Pathway
    (2005) Inestrosa Cantín, Nibaldo; Álvarez Rojas, Alejandra; Pérez-Acle, Tomás
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    Activation of the neuronal c-Abl tyrosine kinase by amyloid-β-peptide and reactive oxygen species
    (2004) Álvarez Rojas, Alejandra; Sandoval, Pablo C.; Leal, Nancy R.; Castro, Paula U.; Kosik, Kenneth S.
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    Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by β-amyloid fibrils
    (2003) Ferrari, G.; Álvarez Rojas, Alejandra; Bronfman A., Miguel L.; Inestrosa Cantín, Nibaldo
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    Amyloid Beta-Peptide Increases BACE1 Translation through the Phosphorylation of the Eukaryotic Initiation Factor-2 alpha
    (2020) Picon Pages, P.; Gutiérrez García, Daniela Andrea; Barranco Almohalla, A.; Crepin, G.; Tajes, M.; Ill-Raga, G.; Guix, F. X.; Menéndez, S.; Arumi Uria, M.; Álvarez Rojas, Alejandra; Vicente, R.; Muñoz, F. J.
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    Amyloid-beta oligomers synaptotoxicity: The emerging role of epha4/c-Abl signaling in Alzheimer's disease
    (2018) Vargas, L. M.; Cerpa Nebott, Waldo Francisco; Munoz, F. J.; Zanlungo Matsuhiro, Silvana; Álvarez Rojas, Alejandra
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    Amyloid-cholinesterase interactions - Implications for Alzheimer's disease
    (2008) Inestrosa Cantín, Nibaldo; Dinamarca Ceballos, Margarita Constanza; Álvarez Rojas, Alejandra
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    Anti-Ribosomal P Protein Autoantibodies From Patients With Neuropsychiatric Lupus Impair Memory in Mice
    (2015) Bravo Zehnder, Marcela; Toledo, Enrique M.; Segovia Miranda, Fabian; Serrano, Felipe G.; Benito, Maria J.; Metz Baer, Claudia Andrea; Retamal, Claudio; Álvarez Rojas, Alejandra; Massardo Vega, Loreto; Inestrosa Cantín, Nibaldo
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    C-ABL estabiliza los niveles de HDAC2 por fosforilación en tirosina reprimiendo la expresión de genes neuronales en la enfermedad de Alzheimer.
    (2014) González Zúñiga, Marcelo Andrés; Álvarez Rojas, Alejandra; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas
    La Enfermedad de Alzheimer (EA) es un desorden neurodegenerativo caracterizado por un deterioro cognitivo progresivo. El sello distintivo de los cerebros afectados con la enfermedad de Alzheimer es la presencia de agregados proteicos insolubles. En este sentido, la hipótesis de la cascada del amiloide plantea que la acumulación y agregación del péptido A\03B2 desencadena un conjunto de mecanismos que conducen a la disfunción y la apoptosis de las neuronas. Entre los mecanismos descritos, uno que ha despertado gran interés es la disminución en la expresión de genes neuronales producto del incremento en los niveles de HDAC2. Esta enzima cataliza la deacetilación de las histonas, lo que provoca que la cromatina adquiera una conformación cerrada que es transcripcionalmente inactiva. Actualmente, la evidencia indica que HDAC2 esta involucrada en el deterioro cognitivo y en la disfunción sináptica que caracteriza a la EA. A pesar de que se ha descrito extensamente que el incremento en los niveles de HDAC2 tiene un papel negativo en el desarrollo de la EA, los mecanismos moleculares involucrados en este incremento no están completamente dilucidados. Interesantemente, se ha demostrado en modelos in vitro que la tirosina quinasa c-Abl esta implicada en la represión de genes por un mecanismo epigenético, el cual sería dependiente de la actividad de las HDACs. En neuronas, la tirosina quinasa c-Abl es un actor clave en los procesos neurodegenerativos. En efecto, resultados de nuestro laboratorio han demostrado que la c-Abl es activada y participa en la muerte neuronal, la disfunción y la pérdida sináptica en modelos de la EA.
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    c-Abl kinase at the crossroads of healthy synaptic remodeling and synaptic dysfunction in neurodegenerative diseases
    (2023) Gutiérrez García, Daniela A.; Chandía Cristi, América Valeska; Yanez, Maria Jose; Zanlungo Matsuhiro, Silvana; Álvarez Rojas, Alejandra
    Our ability to learn and remember depends on the active formation, remodeling, and elimination of synapses. Thus, the development and growth of synapses as well as their weakening and elimination are essential for neuronal rewiring. The structural reorganization of synaptic complexes, changes in actin cytoskeleton and organelle dynamics, as well as modulation of gene expression, determine synaptic plasticity. It has been proposed that dysregulation of these key synaptic homeostatic processes underlies the synaptic dysfunction observed in many neurodegenerative diseases. Much is known about downstream signaling of activated N-methyl-D-aspartate and a-amino-3-hydroxy5-methyl-4-isoazolepropionate receptors; however, other signaling pathways can also contribute to synaptic plasticity and long-lasting changes in learning and memory. The non-receptor tyrosine kinase c-Abl (ABL1) is a key signal transducer of intra and extracellular signals, and it shuttles between the cytoplasm and the nucleus. This review focuses on c-Abl and its synaptic and neuronal functions. Here, we discuss the evidence showing that the activation of c-Abl can be detrimental to neurons, promoting the development of neurodegenerative diseases. Nevertheless, c-Abl activity seems to be in a pivotal balance between healthy synaptic plasticity, regulating dendritic spines remodeling and gene expression after cognitive training, and synaptic dysfunction and loss in neurodegenerative diseases. Thus, c-Abl genetic ablation not only improves learning and memory and modulates the brain genetic program of trained mice, but its absence provides dendritic spines resiliency against damage. Therefore, the present review has been designed to elucidate the common links between c-Abl regulation of structural changes that involve the actin cytoskeleton and organelles dynamics, and the transcriptional program activated during synaptic plasticity. By summarizing the recent discoveries on c-Abl functions, we aim to provide an overview of how its inhibition could be a potentially fruitful treatment to improve degenerative outcomes and delay memory loss.
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    c-Abl links APP-BACE1 interaction promoting APP amyloidogenic processing in Niemann-Pick type C disease
    (2016) Yañez, M.; Belbin, O.; Estrada, L.; Leal, N.; Contreras, P.; Lleó, A.; Burgos, P.; Zanlungo Matsuhiro, Silvana; Álvarez Rojas, Alejandra
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    c-Abl Modulates AICD Dependent Cellular Responses: Transcriptional Induction and Apoptosis
    (2009) Vazquez, M. C.; Vargas Rojas, Lina Marcela; Inestrosa Cantín, Nibaldo; Álvarez Rojas, Alejandra
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    c-Abl Stabilizes HDAC2 Levels by Tyrosine Phosphorylation Repressing Neuronal Gene Expression in Alzheimer's Disease
    (2014) González Zúñiga, Marcelo Andrés; Contreras Soto, Pablo Andrés; Estrada Apablaza, Lisbell; Chamorro Veloso, David Daniel; Villagra, A.; Zanlungo Matsuhiro, Silvana; Seto, E.; Álvarez Rojas, Alejandra
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    C-Abl Tyrosine Kinase Signaling: A New Player in AD Tau Pathology
    (2011) Estrada, L.; Zanlungo Matsuhiro, Silvana; Álvarez Rojas, Alejandra
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    c-Abl/TFEB Pathway Activation as a Common Pathogenic Mechanism in Lysosomal Storage Diseases: Therapeutic Potential of c-Abl Inhibitors
    (2025) Guerra Vergara, Miguel Andrés; Castro Salazar, Juan Francisco; Moreno Torres, Antonio Daniel; Balboa, Elisa; Marugan, Juan J.; Álvarez Rojas, Alejandra; Zanlungo Matsuhiro, Silvana
    Lysosomal storage diseases (LSDs) are characterized by the accumulation of undegraded substrates within lysosomes, often associated with oxidative stress and impaired lysosomal function. In this study, we investigate the role of the c-Abl/TFEB pathway in different LSDs: Gaucher, Niemann-Pick type A (NPA), and Niemann-Pick type C (NPC). Our findings identify c-Abl activation (p-c-Abl) as a common pathogenic mechanism in these disorders. We demonstrate that c-Abl phosphorylates TFEB at Tyr173, leading to its cytoplasmic retention. Using pharmacological models of Gaucher, NPA and NPC in SH-SY5Y neuronal cells and HeLa cells, we assess the effects of the c-Abl inhibitors Imatinib and Neurotinib, as well as the antioxidant α-Tocopherol (α-TOH), on TFEB nuclear translocation and p-c-Abl protein levels. Additionally, we explore the effects of c-Abl inhibitors in cholesterol accumulation in LSDs neuronal models. Our results show that treatment with c-Abl inhibitors or α-TOH promotes TFEB nuclear translocation, enhances lysosomal clearance, and reduces cholesterol accumulation in all three LSD models. These findings highlight the c-Abl/TFEB pathway as a potential therapeutic target for LSDs and potentially other neurodegenerative disorders associated with lysosomal dysfunction.
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    Characterizing HSF1 Binding and Post-Translational Modifications of hsp70 Promoter in Cultured Cortical Neurons : Implications in the Heat-Shock Response
    (2015) Gómez Zúñiga, Andrea Verónica; Córdova, G.; Munita Morgan, Roberto Andrés; Parada, G.; Barrios, Á.; Cancino, G.; Álvarez Rojas, Alejandra; Andrés Coke, María Estela
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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.