Efectos de la fracción enriquecida ZC1 de Zanthoxylum sp. sobre la expresión de proteínas sinápticas y de la mielina en el Modelo Triple Transgénico de Alzheimer

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dc.contributor.advisorSandoval Hernández, Adrián Gabrielspa
dc.contributor.authorSalamanca Valencia, Diana Marcelaspa
dc.contributor.researchgroupMuerte Celularspa
dc.date.accessioned2026-01-21T01:39:31Z
dc.date.available2026-01-21T01:39:31Z
dc.date.issued2025
dc.descriptionilustraciones, diagramasspa
dc.description.abstractLa enfermedad de Alzheimer (EA) es la causa más común de demencia alrededor del mundo, con 55 millones de pacientes, es una enfermedad neurodegenerativa compleja, de origen multifactorial, sin etiología conocida. En el continente americano hay una prevalencia de 6,4% con cerca de cuatrocientos mil pacientes en Colombia. La EA es una enfermedad neurodegenerativa con características histopatológicas clásicas presentando placas amiloides y ovillos neurofibrilares compuestos principalmente por péptidos amiloide y proteína Tau respectivamente, ellos se consideran la causa de la demencia y responsables del deterioro cognitivo. Por su parte, los receptores nucleares X hepáticos (LXR) se han estudiado como blancos terapéuticos para distintas patologías, en modelos murinos de EA producen mejoría cognitiva y cambios en los marcadores histopatológicos acompañados de cambios transcripcionales en múltiples genes. Los productos naturales han sido históricamente la fuente de moléculas bioactivas para el tratamiento de distintas enfermedades, el grupo de investigación de Muerte Celular, Neurociencias y QuiProNaB han realizado una búsqueda activa en el territorio colombiano de especies vegetales con actividad agonista LXR, encontrado extractos activos del género Zanthoxylum, donde se han obtenido una fracción enriquecida en agonistas LXR, denominado (ZC1) con compuestos claramente establecidos. Se ha demostrado que el tratamiento farmacológico con ZC1 en animales triple transgénicos de la EA (3xTg), produce mejoría cognitiva y reduce la carga amiloide y Tau. Con el objetivo de establecer cambios moleculares que expliquen la mejora cognitiva, se evaluó la expresión de proteínas sinápticas y mielina en animales 3xTg tratados con ZC1 Metodología: Rodajas de cerebro de ratones 3xTg de 17 meses de edad, tratados con ZC1 durante 70 días, fueron sometidas a inmunomarcación con anticuerpos dirigidos contra proteínas asociadas a la función sináptica: sinapsina I (Syn1), transportador vesicular de glutamato 1 (VGLUT1), proteína de densidad postsináptica 95 (PSD-95), subunidad 2B del receptor NMDA (NMDAR2B) y proteínas SHANK. Además, se emplearon anticuerpos contra la proteína básica de mielina (MBP), el factor de transcripción de oligodendrocitos (OLIG2) y el marcador neuronal de neuronas maduras (NeuN). Las muestras fueron analizadas mediante microscopía confocal. Resultados: Se observó que el tratamiento con ZC1 en animales 3xTg respecto a los tratados con vehículo; produjo cambios asociado al aumento de SYN en todas las áreas del hipocampo, siendo más notorio en subículo y corteza entorrinal. VGLU1 también presentó un aumento significativo en DG, CA3, subículo y corteza entorrinal. De la misma forma, PSD 95 mostró un incremento significativo DG, CA3, subículo y corteza entorrinal. Asimismo, SHANK presentaron aumento en CA3, subículo y corteza entorrinal, y NMDA2B incrementó en áreas de DG, subículo y corteza entorrinal. Finalmente, MBP y Olig2 mostró un incremento en CA3 y corteza entorrinal y NeuN presentó un aumento en todo el hipocampo en especialmente en CA3, CA1 y corteza entorrinal. Conclusión: Los hallazgos de esta investigación mostraron que las moléculas presentes en la fracción enriquecida ZC1 contribuyen a preservar la integridad sináptica mediante el aumento en la expresión de proteínas sinápticas y la conservación de la mielina, generando así un efecto protector tanto en oligodendrocitos como en neuronas maduras, explicando las mejoras cognitivas observadas en 3xTg. En conjunto, estos resultados refuerzan el potencial terapéutico de la fracción enriquecida ZC1 en el contexto de la enfermedad de Alzheimer. (Texto tomado de la fuente).spa
dc.description.abstractAlzheimer’s disease (AD) is the most common cause of dementia worldwide, affecting approximately 55 million patients. It is a complex neurodegenerative disorder of multifactorial origin with no known etiology. In the Americas, its prevalence is estimated at 6.4%, with nearly 400,000 patients in Colombia. AD is characterized by classical histopathological features, including amyloid plaques and neurofibrillary tangles composed primarily of amyloid-β peptides and Tau protein, respectively, both of which are considered central contributors to dementia and cognitive decline. Liver X receptors (LXR), members of the nuclear receptor family, have been investigated as therapeutic targets for various pathologies. In murine models of AD, their activation has been shown to improve cognition and modify histopathological markers, alongside transcriptional changes in multiple genes. Natural products have historically represented a major source of bioactive molecules for the treatment of diverse diseases. The Cell Death, Neuroscience, and QuiProNaB research groups have conducted an active search across Colombia for plant species with LXR agonist activity, identifying active extracts from the Zanthoxylum genus. From these, an enriched fraction containing well-defined LXR agonists, termed ZC1, was obtained. Pharmacological treatment with ZC1 in triple-transgenic AD (3xTg) mice has previously been shown to improve cognition and reduce amyloid and Tau pathology. Objective: To identify molecular changes that may underlie the cognitive improvements induced by ZC1, we evaluated the expression of synaptic and myelin-related proteins in 3xTg mice treated with this fraction. Methods: Brain slices from 17-month-old 3xTg mice treated with ZC1 for 70 days were subjected to immunolabeling with antibodies targeting proteins associated with synaptic function: synapsin I (Syn1), vesicular glutamate transporter 1 (VGLUT1), postsynaptic density protein 95 (PSD-95), NMDA receptor subunit 2B (NMDAR2B), and SHANK proteins. Additional antibodies were used against myelin basic protein (MBP), the oligodendrocyte transcription factor Olig2, and the neuronal marker for mature neurons NeuN. Samples were analyzed using confocal microscopy. Results: Treatment with ZC1 in 3xTg mice, compared with vehicle-treated controls, produced marked changes in protein expression. Specifically, SYN expression increased across all hippocampal regions, most prominently in the subiculum and entorhinal cortex. VGLUT1 levels were significantly elevated in the dentate gyrus (DG), CA3, subiculum, and entorhinal cortex. Similarly, PSD95 showed significant increases in the DG, CA3, subiculum, and entorhinal cortex. SHANK proteins were upregulated in CA3, subiculum, and entorhinal cortex, while NMDAR2B expression increased in the DG, subiculum, and entorhinal cortex. Regarding myelinassociated markers, MBP and Olig2 levels increased in CA3 and the entorhinal cortex. Finally, NeuN expression was elevated throughout the hippocampus, particularly in CA3, CA1, and the entorhinal cortex. Conclusion: The findings of this study demonstrate that bioactive molecules present in the ZC1-enriched fraction contribute to the preservation of synaptic integrity by enhancing the expression of synaptic proteins and supporting myelin maintenance. This dual action exerts a protective effect on both oligodendrocytes and mature neurons, thereby providing a molecular basis for the cognitive improvements observed in 3xTg mice. Taken together, these results reinforce the therapeutic potential of the ZC1-enriched fraction in the context of Alzheimer’s disease.eng
dc.description.degreelevelMaestríaspa
dc.description.degreenameMagíster en Neurocienciasspa
dc.description.methodsRodajas de cerebro de ratones 3xTg de 17 meses de edad, tratados con ZC1 durante 70 días, fueron sometidas a inmunomarcación con anticuerpos dirigidos contra proteínas asociadas a la función sináptica: sinapsina I (Syn1), transportador vesicular de glutamato 1 (VGLUT1), proteína de densidad postsináptica 95 (PSD-95), subunidad 2B del receptor NMDA (NMDAR2B) y proteínas SHANK. Además, se emplearon anticuerpos contra la proteína básica de mielina (MBP), el factor de transcripción de oligodendrocitos (OLIG2) y el marcador neuronal de neuronas maduras (NeuN). Las muestras fueron analizadas mediante microscopía confocalspa
dc.description.researchareaEnfermedades neurodegenerativasspa
dc.format.extentxvi, 115 páginasspa
dc.format.mimetypeapplication/pdf
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/89276
dc.language.isospa
dc.publisherUniversidad Nacional de Colombiaspa
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotáspa
dc.publisher.facultyFacultad de Medicinaspa
dc.publisher.programBogotá - Medicina - Maestría en Neurocienciasspa
dc.relation.indexedBiremespa
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.licenseAtribución-NoComercial-SinDerivadas 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc570 - Biología::572 - Bioquímicaspa
dc.subject.ddc610 - Medicina y salud::616 - Enfermedadesspa
dc.subject.decsProteína Básica de Mielinaspa
dc.subject.decsMyelin Basic Proteineng
dc.subject.decsSinapsinasspa
dc.subject.decsSynapsinseng
dc.subject.decsReceptores Citoplasmáticos y Nuclearesspa
dc.subject.decsReceptors, Cytoplasmic and Nucleareng
dc.subject.proposalProteínas sinápticasspa
dc.subject.proposalLXRspa
dc.subject.proposalZanthoxylumspa
dc.subject.proposalZC1spa
dc.subject.proposal3xTgspa
dc.subject.proposalProteínas sinápticasspa
dc.subject.proposalMielinaspa
dc.subject.proposalOligodendrocitos neuronasspa
dc.subject.proposalAlzheimer’s diseaseeng
dc.subject.proposalLXReng
dc.subject.proposalZanthoxylumeng
dc.subject.proposalZC1eng
dc.subject.proposal3xTgeng
dc.subject.proposalSynaptic proteinseng
dc.subject.proposalMyelineng
dc.subject.proposalOligodendrocyteseng
dc.subject.proposalNeuronseng
dc.titleEfectos de la fracción enriquecida ZC1 de Zanthoxylum sp. sobre la expresión de proteínas sinápticas y de la mielina en el Modelo Triple Transgénico de Alzheimerspa
dc.title.translatedEffects of the ZC1-enriched fraction of Zanthoxylum sp. on synaptic and myelin protein expression in the Triple Transgenic Alzheimer's Modeleng
dc.typeTrabajo de grado - Maestríaspa
dc.type.coarhttp://purl.org/coar/resource_type/c_bdcc
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.contentText
dc.type.driverinfo:eu-repo/semantics/masterThesis
dc.type.redcolhttp://purl.org/redcol/resource_type/TM
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dcterms.audience.professionaldevelopmentEstudiantesspa
dcterms.audience.professionaldevelopmentInvestigadoresspa
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2

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