[vc_row][vc_column][vc_tta_accordion shape=\u00bbsquare\u00bb c_icon=\u00bbchevron\u00bb c_position=\u00bbright\u00bb active_section=\u00bb\u00bb no_fill=\u00bbtrue\u00bb collapsible_all=\u00bbtrue\u00bb][vc_tta_section title=\u00bbResumen\u00bb tab_id=\u00bbresumen\u00bb][vc_column_text]<\/p>\n
El envejecimiento poblacional y la patolog\u00eda tipo Alzheimer (EA, la demencia de mayor incidencia en la poblaci\u00f3n de edad avanzada) constituyen una de las prioridades en los retos en salud de la Uni\u00f3n Europea. Elucidar los desencadenantes de procesos de envejecimiento cerebral es de gran importancia para efectuar intervenciones preventivas y paliativas que contribuyan a la calidad de vida en la tercera edad. En este proyecto, investigaremos p73 (factor de transcripci\u00f3n preponderante en la regulaci\u00f3n de la muerte neuronal) en la modulaci\u00f3n de la prote\u00edna reelin. Reelin es de importancia crucial en la plasticidad sin\u00e1ptica, las funciones cognitivas y la supervivencia neuronal, durante el desarrollo y en el cerebro adulto. Recientemente, se ha demostrado un papel de esta prote\u00edna en neuroprotecci\u00f3n frente a EA a\u00fan por elucidar, que ser\u00e1 investigado en este proyecto. Utilizando un modelo knock-out de rat\u00f3n para p73, hemos observado anteriormente que estos ratones presentan degeneraci\u00f3n cerebral aguda mientras que, parad\u00f3jicamente, son extremadamente longevos. Estos datos sugieren una dualidad de p73 en la muerte celular, si bien se desconocen los mecanismos moleculares implicados en este fen\u00f3meno, que nos proponemos caracterizar. Por otra parte, hemos demostrado previamente que alteraciones lip\u00eddicas de microdominios de membrana neuronal lipid raft se modifican durante el envejecimiento neuronal, y son desencadenantes de procesos neuropatol\u00f3gicos desde fases asintom\u00e1ticas de EA. Nuestras observaciones preliminares indican que p73 se ubica en lipid rafts, y podr\u00eda tener un papel importante en la homeostasis de los mismos, a\u00fan por demostrar. En este proyecto, investigaremos la posible modulaci\u00f3n de factores de supervivencia neuronal y de eventos moleculares tempranos durante el envejecimiento cerebral y en procesos de desarrollo de EA asociados a la regulaci\u00f3n de p73, y la implicaci\u00f3n de alteraciones en la homeostasis de los lipid raft. Utilizaremos muestras de cerebro humano, modelos murinos KOp73, de envejecimiento acelerado y de patolog\u00eda tipo EA, cultivos neuronales, y muestras de l\u00edquido cefalorraqu\u00eddeo procedentes de pacientes con EA en diferentes estad\u00edos. Mediante diversas aproximaciones morfol\u00f3gicas, bioqu\u00edmicas y metab\u00f3licas pretendemos: a) Caracterizar los mecanismos potenciales de regulaci\u00f3n de p73 en prote\u00ednas relevantes para la supervivencia neuronal, reelin y klotho, receptores neurotr\u00f3ficos del factor de crecimiento insulinotr\u00f3pico y de los estr\u00f3genos, IGF-1R y ER;, y su relaci\u00f3n con procesos neurodegenerativos en Alzheimer; b) elucidar la posible influencia de alteraciones de los lipid raft en la actividad de estas prote\u00ednas durante el envejecimiento neuronal; c) identificar los eventos moleculares y metab\u00f3licos en lipid rafts asociados con los marcadores proteicos del estudio, en muestras de l\u00edquido cefalorraqu\u00eddeo y exosomas extra\u00eddos de pacientes en diferentes fases de Alzheimer. Los abordajes propuestos permitir\u00e1n caracterizar aspectos relevantes del envejecimiento cerebral y neuropatolog\u00edas asociadas, y proporcionar\u00e1n herramientas innovadoras en el diagn\u00f3stico precoz. Adem\u00e1s, se espera que los resultados nos permitan comprender los cambios moleculares y celulares en las c\u00e9lulas nerviosas asociados al envejecimiento, como detonantes de procesos neurodegenerativos.<\/p>\n
[\/vc_column_text][\/vc_tta_section][vc_tta_section title=\u00bbAbstract\u00bb tab_id=\u00bbabstract\u00bb][vc_column_text]<\/p>\n
Population ageing and pathologies such as Alzheimer (AD, the dementia with the highest incidence in aged people) constitute one of the priorities in health challenges in the European Union. It is of great importance to elucidate the events triggering brain ageing to ultimately elaborate proceedings that may contribute to the quality of life in the elderlies. In this project, we will investigate p73 (a transcription factor that plays a primordial role in neuronal death) in the modulation of reelin. Reelin is of crucial importance in the synaptic plasticity, cognitive functions, and neuronal survival during, both, development and adult brain. Recently, it has been demonstrated a role of reelin in neuroprotection against AD that still remains to be elucidated. This aspect will be investigated in this project. Using a p73 knock-out murine model, we have previously observed that these mice show acute brain degeneration whereas, paradoxically, these mice are extremely long-lived. These data demonstrate a duality of p73 in cell death, although it is unknown the mechanisms involved in this phenomenon, that we propose to characterize here. Moreover, we have previously demonstrated that lipid alterations in neuronal membrane microdomains named lipid rafts are modified during normal neuronal ageing. These alterations trigger some neuropathological processes since asymptomatic stages of AD. Our preliminary observations indicate that p73 is located in lipid rafts, where it may have an important role in raft homeostasis, still to be investigated. In the present Project, we will investigate the potential modulation of neuronal survival factors, and the early molecular events during normal brain ageing, and in the development of pathological AD processes associated with the regulation of p73, as well as the involvement of aberrant anomalies in the homeostasis of lipid rafts. For this study, we will use human brain samples, murine models Kop73, of accelerated ageing and APP transgenic mice, neuronal cultures, and cerebrospinal fluid samples from patients at different stages of Alzheimers disease. Using different morphological, biochemical and metabolic approaches, we intend: a) To characterize the potential mechanisms of p73 regulation in relevant proteins for neuronal survival, such as reelin and klotho, neurotrophic receptors of insulin growth factor and estrogens, IGF-1R and ER, and its correlation with Alzheimer neurodegenerative processes; b) to elucidate the potential influence of alterations in lipid raft microdomains in the activity of these proteins during neuronal ageing; c) to identify the molecular and metabolic events in lipid rafts associated with the protein markers of the study, using cerebrospinal fluid samples and exosomes isolated from Alzheimers disease patients at different stages. The proposed approaches will allow us to characterize relevant aspects of brain ageing and the associated neuropathologies, and will provide innovative tools for early diagnosis. Moreover, it is expected that these results will allow understanding the molecular and cellular changes taking place in neural cells associated with ageing, as hallmarks of neurodegenerative processes<\/p>\n
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