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Alzheimer's disease neurotoxic peptides : towards a comprehension of their modes of action on model membranes.

Abstract : Alzheimer’s disease is a complex neuropathological disorder that constitutes the prime form of dementia. Intimately related to ageing, it is associated to the gradual loss of memory and cognitive functions in individual suffering from the pathology. With nearly 30 million people concerned today, and the alarming trends predicting this figure to increase fourfold by 2050, Alzheimer’s disease will constitute a major burden for our societies in the upcoming decades. The cerebral atrophy occurring within the brain results from slow and progressive neurodegenerative mechanisms triggered many years before the appearance of the first symptoms. Two histopathological markers have been identified as strongly associated to the neurodegeneration: the senile plaques, majorly composed of the amyloid peptide Abeta, and the neurofibrillary tangles, constituted of the abnormally phosphorylated form of Tau protein. These two molecules, hence considered as the main culprits of the disease, are therefore under the spotlight of researchers who try to better understand the respective roles in the neurodegeneration process and uncover therapeutic solutions to a still uncurable disease.One of the promising research axis is focusing on the interplay between these molecules and the plasma membrane as potential interactions could convincingly rationalize the neural cell deaths if they happened to be deleterious. Therefore, investigate these interactions in detail is of primary importance to identify the factors that might drive Abeta and Tau to cause damages on membranes. A strong body of evidences has demonstrated that certain lipids could promote these interactions and are then suspected to be involved into detrimental phenomena. However, numerous results appear to be contradicting and consensual conclusions are still lacking.This PhD was dedicated to the investigation of the effects of Abeta and K18, a key peptide fragment of Tau protein, on membranes with a particular focus on the influence of lipids. The aim of this work was to elucidate the action mechanisms of these peptides.To first comprehend how membrane damages can be induced, we first focused on the solubilising ability of extensively used amphiphile agents: detergents. As a first study, we revealed that the membrane composition and the physicochemical properties of lipids play an important role in driving the solubilisation of the bilayer, a process that can even lead to a selectivity during the lipid extraction.The core part of the project was to visualize the effects of the amyloid peptides Abeta and K18 on supported lipid bilayers as membrane models, using atomic force microscopy as an investigation technique. With its high spatial resolution and its ability to operate in physiological milieu, this approach has shown that the membrane composition could promote membrane disruption induced by Abeta oligomers in a lipid-dependent manner. More importantly, we propose that packing defects at the interface of membrane domains act as adsorption and nucleation sites leading to membrane damages.Using the same strategy, we observed that K18 could also induce solubilisation phenomenon and demonstrated to be sensitive to the aspect of lipid order in membranes.In both cases, we highlighted that these peptides could be detrimental to supported lipid bilayers and that their disruptive abilities, associated to detergent-like mechanisms, were intimately dependent of lipids. We also show that the aggregation, a phenomenon that can lead to the peptides fibrillation can only be triggered in presence of certain lipids.This work provides important insights about the decisive role of membrane composition in modulating interactions with the Abeta and K18. This interplay could constitute one of the numerous factors that promote neurotoxic phenomena, taking part in the complex neurodegenerative processes associated to Alzheimer’s disease.
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Mehdi Azouz. Alzheimer's disease neurotoxic peptides : towards a comprehension of their modes of action on model membranes.. Analytical chemistry. Université de Bordeaux; Université de Montréal, 2019. English. ⟨NNT : 2019BORD0419⟩. ⟨tel-02502714⟩



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