Cambios en los niveles de expresión de SVCT2 en presencia de oligómeros del péptido aβ en modelos de la enfermedad de Alzheimer.
Loading...
Date
2024
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Universidad de Concepción
Abstract
La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo caracterizado la acumulación de oligómeros solubles del péptido β-amiloide (AβOs) que provocan efectos deletéreos como estrés oxidativo y disfunción mitocondrial. La vitamina C, un antioxidante fundamental, desempeña un papel protector en la preservación de la integridad y función mitocondrial. Sin embargo, el mecanismo por el cual se transporta a las mitocondrias, especialmente en neuronas afectadas por la EA, aun no se comprende completamente. Si bien se ha propuesto que la vitamina C ingresa a la células principalmente como ácido deshidroascórbico (DHA) mediante transportadores de glucosa (GLUTs), investigaciones recientes indican que el transportador de vitamina C dependiente de sodio 2 (SVCT2), típicamente localizado en la membrana plasmática, también podría localizarse en las mitocondrias y medias el transporte de vitamina C en su forma reducida, ácido ascórbico (AA).
La presente tesis busca investigar el papel de SVCT2 en neuronas hipocampales de ratón y células CAD diferenciadas expuestas a AβOs, con el objetivo de determinar si SVCT2 se localiza en las mitocondrias y si su expresión se ve afectada por el estrés inducido por los AβOs. A través de cultivos primarios de neuronas hipocampales de ratón y de modelos celulares, se evaluó la expresión y localización de SVCT2 en respuesta a concentraciones crecientes de AβOs. El estudio reveló un aumento significativo en la expresión de una variante corta de SVCT2, que podría representar una forma dominante-negativa, en neuronas tratadas con AβOs, lo que podría agravar el daño oxidativo al afectar el transporte de vitamina C. Además, en tejidos cerebrales de pacientes con enfermedades neurodegenerativas avanzadas, se detectó una señal débil de SVCT2, posiblemente debido a la marcada pérdida de neuronas.
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of soluble amyloid-β oligomers (AβOs), which cause deleterious effects such as oxidative stress and mitochondrial dysfunction. Vitamin C, an important antioxidant, plays a protective role in maintaining mitochondrial integrity and function, but its transport into mitochondrial, particularly in neurons affected by AD, remains unclear. While previous studies suggest that vitamin C enters the cells primarily as dehydroascorbic acid (DHA) via glucose transporters (GLUTs), recent findings indicate that the sodium-dependent vitamin C transporter 2 (SVCT2), typically located in the plasma membrane, may also localize to mitochondria and mediate the transport of vitamin C in its reduced form, ascorbic acid (AA). This thesis aims to investigate the role of SVCT2 in hippocampal neurons and CAD cells exposed to AβOs to determine whether SVCT2 localizes to mitochondria and how its expression is affected by AβO-induced stress. Using primary mouse hippocampal neurons and cellular models, we evaluated SVCT2 expression and localization in response to increasing concentrations of AβOs. The study reveals a significant upregulation of a short SVCT2 variant, potentially a dominant-negative form, in neurons tested with AβO, which may exacerbate oxidative damage by impairing vitamin C transport. In addition, brain tissues from patients with advanced neurodegenerative diseases showed a weak signal of SVCT2, likely due to the marked loss of neurons.
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of soluble amyloid-β oligomers (AβOs), which cause deleterious effects such as oxidative stress and mitochondrial dysfunction. Vitamin C, an important antioxidant, plays a protective role in maintaining mitochondrial integrity and function, but its transport into mitochondrial, particularly in neurons affected by AD, remains unclear. While previous studies suggest that vitamin C enters the cells primarily as dehydroascorbic acid (DHA) via glucose transporters (GLUTs), recent findings indicate that the sodium-dependent vitamin C transporter 2 (SVCT2), typically located in the plasma membrane, may also localize to mitochondria and mediate the transport of vitamin C in its reduced form, ascorbic acid (AA). This thesis aims to investigate the role of SVCT2 in hippocampal neurons and CAD cells exposed to AβOs to determine whether SVCT2 localizes to mitochondria and how its expression is affected by AβO-induced stress. Using primary mouse hippocampal neurons and cellular models, we evaluated SVCT2 expression and localization in response to increasing concentrations of AβOs. The study reveals a significant upregulation of a short SVCT2 variant, potentially a dominant-negative form, in neurons tested with AβO, which may exacerbate oxidative damage by impairing vitamin C transport. In addition, brain tissues from patients with advanced neurodegenerative diseases showed a weak signal of SVCT2, likely due to the marked loss of neurons.
Description
Tesis presentada para optar al grado de Magíster en Neurobiología
Keywords
Enfermedades neurodegenerativas, Enfermedad de Alzheimer, Expresión génica