Mort cellulaire et maladie d'Alzheimer : mécanismes moléculaires impliqués dans l'apoptose neuronale induite par le peptide [bêta]-amyloïde (A[bêta]) sous forme soluble et facteurs protecteurs associés

Abstract : For two decades, the predominant theory in the research related to Alzheimer's Disease (AD) has consisted in the amyloid cascade hypothesis, causally linking the AB peptide aggregation to the pathological characteristics associated to AD. Many studies, including ours, suggest that the aggregation of the peptides as a causal element of the pathology should be reconsidered in favour of a crucial role played by the soluble oligomers of AB. The aim of this study is to analyse the neurodegenerative processes involved in AD by focusing on the molecular and cellular mechanisms triggered by the soluble oligomers of AB(1-40142). We highlight the in vitro fusogenic properties of the soluble AB peptides, which are responsible for the neurotoxicity of the peptides due to their specific interaction with the plasma membrane. By modulating the membrane fluidity, the soluble AB peptides entail a caspase-3, -9 and calpain-dependent apoptosis, inducing an oxidative stress and an early perturbation of the microtubule network (MTs). We show that, by enriching the membrane with cholesterol, the susceptibility of the neurons to the soluble AB peptides is inhibited. Among the intracellular targets serving as explanations for the MTs perturbation, we have proved that the soluble AB peptides entai1 the overexpression of the tau protein, independently of its phosphorylation state, associated with a degradation of the MAP1A, MAP1B proteins and of the three isoforms of MAP2 (2a, 2b, 2c). These perturbations linked to the MTS have a major impact on the setting-up of the vesicular traffic and on the subsequent neuronal apoptosis.
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Theses
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http://docnum.univ-lorraine.fr/prive/SCD_T_2006_0240_FIFRE.pdf
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https://hal.univ-lorraine.fr/tel-01746994
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Submitted on : Thursday, March 29, 2018 - 10:49:10 AM
Last modification on : Friday, March 30, 2018 - 1:28:55 AM

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  • HAL Id : tel-01746994, version 1

Citation

Alexandre Fifre. Mort cellulaire et maladie d'Alzheimer : mécanismes moléculaires impliqués dans l'apoptose neuronale induite par le peptide [bêta]-amyloïde (A[bêta]) sous forme soluble et facteurs protecteurs associés. Sciences agricoles. Université Henri Poincaré - Nancy 1, 2006. Français. ⟨NNT : 2006NAN10240⟩. ⟨tel-01746994⟩

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