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Population aging and Alzheimer's disease (AD, the most common dementia in the elderly) are among the top health challenges facing the European Union. Elucidating the triggers of brain aging processes is crucial for implementing preventive and palliative interventions that contribute to quality of life in old age. In this project, we will investigate p73 (a key transcription factor in regulating neuronal death) in the modulation of the reelin protein. Reelin is crucial for synaptic plasticity, cognitive function, and neuronal survival during development and in the adult brain. Recently, a role for this protein in neuroprotection against AD has been demonstrated, though it remains to be fully elucidated, and this will be investigated in this project. Using a p73 knockout mouse model, we have previously observed that these mice exhibit acute brain degeneration while, paradoxically, being extremely long-lived. These data suggest a dual role for p73 in cell death, although the molecular mechanisms involved in this phenomenon are unknown, and we propose to characterize them. Furthermore, we have previously demonstrated that lipid alterations in neuronal membrane microdomains (lipid rafts) are modified during neuronal aging and trigger neuropathological processes from asymptomatic phases of Alzheimer's disease (AD). Our preliminary observations indicate that p73 is located in lipid rafts and could play an important role in their homeostasis, a role yet to be demonstrated. In this project, we will investigate the possible modulation of neuronal survival factors and early molecular events during brain aging and in AD developmental processes associated with p73 regulation, and the involvement of alterations in lipid raft homeostasis. We will use human brain samples, KOp73 murine models of accelerated aging and AD-like pathology, neuronal cultures, and cerebrospinal fluid samples from AD patients at different stages. Through various morphological, biochemical, and metabolic approaches, we aim to: a) characterize the potential regulatory mechanisms of p73 in proteins relevant to neuronal survival, reelin and klotho, neurotrophic receptors for insulin-like growth factor and estrogens, IGF-1R and ER, and their relationship with neurodegenerative processes in Alzheimer's disease; b) elucidate the possible influence of lipid raft alterations on the activity of these proteins during neuronal aging; and c) identify the molecular and metabolic events in lipid rafts associated with the study's protein markers in cerebrospinal fluid and exosome samples extracted from patients in different stages of Alzheimer's disease. The proposed approaches will allow us to characterize relevant aspects of brain aging and associated neuropathologies, and will provide innovative tools for early diagnosis. Furthermore, the results are expected to enable us to understand the molecular and cellular changes in nerve cells associated with aging, as triggers for neurodegenerative processes.
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Population aging 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 aging 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 primary 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, which we propose to characterize here. Furthermore, we have previously demonstrated that lipid alterations in neuronal membrane microdomains named lipid rafts are modified during normal neuronal aging. 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 aging, 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 aging 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 aging; 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 aging and the associated neuropathologies, and will provide innovative tools for early diagnosis. Furthermore, it is expected that these results will allow understanding the molecular and cellular changes taking place in neural cells associated with aging, as hallmarks of neurodegenerative processes
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