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Tabla de Contenidos: “…Summary -- Introduction -- 1.1 Protein aggregation and amyloidoses -- 1.1.1 Mechanisms of amyloid fibril formation -- 1.1.2 Oligomer structural polymorphism: fibrillar and prefibrillar oligomers -- 1.1.3 Oligomer toxicity: common mechanism of pathogenesis -- 1.1.4 Amyloid formation is an inherent property of polypeptide chains: functional amyloid and disease unreleated amyloid -- 1.2 HypF-N: model protein of amyloid aggregation unrelated to disease -- 1.2.1 Function, structure and aggregation of HypF-N -- 1.2.2 HypF-N protofibrils interact with cell membranes originating a cytotoxic cascade -- 1.2.3 A causative link between the structure of HypF-N oligomers and their ability to cause cellular dysfunction -- 1.3 Alzheimer's disease -- 1.3.1 The Alzheimer phenotype -- 1.3.2 The elaborate processing of APP -- 1.3.3 The genetics of Alzheimer's disease -- 1.3.4 Peripheral cells as a tool to identify and test hypotheses on AD pathophysiology -- 1.3.5 Adult neurogenesis and stem cell technology for AD -- 1.4 Cholesterol and gangliosides in the central nervous system (CNS) -- 1.4.1 Brain cholesterol metabolism -- 1.4.2 Ganglioside metabolism -- 1.4.3 Lipid rafts -- 1.4.4 Role of cholesterol in AD -- 1.4.5 Role of gangliosides in AD -- 1.5 Aim of the study -- Materials & Methods -- 2.1 Materials -- 2.1.1 Chemicals -- 2.1.2 Fluorescent probes -- 2.1.3 Peptides and aggregation protocols -- 2.2 Cell cultures -- 2.3 Methods -- 2.3.1 Separation processes -- 2.3.2 Differentiation of human mesenchymal stromal cells -- 2.3.3 Modulation of membrane cholesterol levels -- 2.3.4 Modulation of membrane GM1 levels -- 2.3.5 Cholesterol content measurements -- 2.3.6 GM1 content measurements -- 2.3.7 Cell exposure to peptide aggregates -- 2.3.8 Analysis of aggregate interaction with the cells -- 2.3.9 Analysis of aggregate interaction with GM1 -- 2.3.10 Analysis of aggregate internalisation -- 2.3.11 Analysis of membrane permeability -- 2.3.12 Analysis of cytosolic Ca2+ dyshomeostasis -- 2.3.13 Evaluation of ROS production -- 2.3.14 Analysis of lipid peroxidation -- 2.3.15 Cytotoxicity assay and cell death analysis: apoptotic and necrotic markers -- 2.3.16 Steady-state fluorescence anisotropy -- 2.3.17 Atomic force microscopy (AFM) -- 2.3.18 Measurements of the fluorescence intensities -- 2.3.19 Statistical analysis -- Results -- 3.1 Results I -- 3.1.1 A protective role for lipid raft cholesterol against amyloidinduced membrane damage in human neuroblastoma cells -- 3.1.2 Aß42 oligomer binding to the cell surface and its cytotoxic effect are modulated by membrane cholesterol content -- 3.1.3 Aß42 oligomers colocalize with lipid rafts -- 3.1.4 Isolation and characterization of DRMs -- 3.1.5 Effects of ADDLs on lipid raft structural order -- 3.1.6 AFM imaging of supported DRMs purified from cells exposed to ADDLs -- 3.2 Results II -- 3.2.1 Lipid rafts mediate amyloid-induced calcium dyshomeostasis and oxidative stress in Alzheimer's disease -- 3.2.2 Lipid rafts are primary interaction sites for Aß42 oligomers at the plasma membrane -- 3.2.3 Cholesterol and GM1 mediate Aß42 accumulation at the plasma membrane -- 3.2.4 Cholesterol and GM1 mediate Ca2+ dyshomeostasis and extensive membrane permeabilization induced by Aß42 oligomers -- 3.2.5 GM1 modulates lipid peroxidation and cytotoxicity induced by Aß42 oligomers -- 3.2.6 GM1 mediates Aß42-induced Ca2+ dyshomeostasis, lipid peroxidation and cytotoxicity in rat cortical neurons -- 3.3 Results III -- 3.3.1 Membrane lipid composition and its physicochemical properties define cell vulnerability to aberrant protein oligomers -- 3.3.2 Membrane cholesterol content modulates oligomer cytotoxicity -- 3.3.3 Membrane cholesterol modulates oligomer-induced alteration of intracellular Ca2+ homeostasis and ROS levels -- 3.3.4 Cholesterol levels modulate membrane permeability to the oligomers -- 3.3.5 Membrane GM1 affects the cytotoxic and permeabilizing effects of HypF-N oligomers -- 3.3.6 GM1, rather than cholesterol, plays a dominant role in oligomer cytotoxicity and membrane permeability -- 3.4 Results IV -- 3.4.1 Neuronal differentiation of human mesenchymal stromal cells increases their resistance to Aß42 aggregate toxicity -- 3.4.2 Neuronal differentiation of hMSCs results in reduced levels of membrane GM1 -- 3.4.3 Neuronal differentiation of hMSCs reduces the interaction of Aß42 oligomers with the cell surface -- 3.4.4 Neuronal differentiation of hMSCs reduces Aß42 oligomerinduced intracellular Ca2+ dyshomeostasis and oxidative stress -- 3.4.5 Neuronal differentiation of hMSCs increases cell resistance to Aß42 aggregates Discussion -- 4.1 A protective role for lipid raft cholesterol against amyloid-induced membrane damage in human neuroblastoma cells -- 4.2 Lipid rafts mediate amyloid-induced calcium dyshomeostasis and membrane permeabilization in Alzheimer's fibroblasts -- 4.3 Membrane lipid composition and its physicochemical properties define cell vulnerability to aberrant protein oligomers -- 4.4 Neuronal differentiation of human mesenchymal stromal cells increases their resistance to Aß42 aggregate toxicity -- 4.5 Concluding remarks -- Abbreviations -- References…”

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