Ce chapitre bibliographique illustre bien la complexité des mécanismes pathogéniques de la maladie d’Alzheimer. Les difficultés rencontrées par la communauté scientifique pour élucider l’origine étiologique, probablement multifactorielle, de la maladie a conduit à un élargissement, voir à une dispersion, de l’éventail des stratégies thérapeutiques. Une meilleure compréhension des mécanismes de développement de la maladie est donc nécessaire pour mieux cibler la recherche de traitements curatifs.
Dans cette thèse, nous nous sommes basé sur l’hypothèse principale de la cascade amyloïde. L’ensemble des études présentées s’articule donc autour du peptide amyloïde bêta. D’autre part, il est important de comprendre le rôle joué par les ions métalliques (en particulier zinc et cuivre) dans la maladie d’Alzheimer. En effet, leur implication semble essentielle puisqu’ils prennent part à l’agrégation et probablement à la toxicité d’Aβ. Ainsi l’étude de l’affinité du peptide amyloïde bêta pour ces métaux (chapitre 2) s’inscrit logiquement dans cette optique. Elle est de plus nécessaire à l’élaboration de stratégies thérapeutiques par chélation des métaux.
Nous nous sommes ensuite focalisés sur le zinc, dont l’interaction avec Aβ a été moins étudiée que le cuivre. Le zinc a été rapporté induire l’agrégation d’Aβ. Afin d’expliquer cette influence et de saisir sa pertinence vis-à-vis de la formation des fibres amyloïdes, il nous a semblé important de rechercher l’existence d’éventuelles espèces intermédiaires (chapitre 3) et de déterminer leur structure secondaire (chapitre 4).
La provenance des quantités élevées de zinc dans les plaques amyloïdes reste encore à élucider. Ainsi, l’hypothèse d’une interaction avec la métallothionéine-3, protéine à zinc très répandue dans le cerveau, a été explorée au chapitre 5.
Enfin, d’un point de vue de la toxicité, une des voies envisagées dans la littérature consistant en la formation de pores d’Aβ dans les membranes cellulaires, a été analysée au chapitre 6 en prenant compte de l’influence du zinc.
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