Nouvelles preuves de concept pour la chélatothérapie contre la maladie d'Alzheimer : études spectroscopiques des interactions entre les ions cuivre et zinc

Abstract : Alzheimer's disease is a neurodegenerative disease, affecting more than 30 million people all over the world. Nowadays, only symptomatic therapies exist, there is no cure yet. A dyshomeostasis of metal ions such as Cu and Zn ions in some areas of the brain is one of the different hypothesis about this disease. They would promote an accumulation of peptides, the Amyloid-ß (Aß) peptides, in the synaptic cleft. These aggregates would prevent the neuronal connections, triggering known symptoms of the disease, such as memory loss or cognitive impairments. Cu ions would also be responsible for an important oxidative stress, destroying the neuronal membranes for example. Cu ions are an important therapeutic target to cure the disease. Investigations are currently focusing on the development of new molecules, called chelators, in order to remove selectively Cu ions (over Zn ions), to regulate their concentrations and avoid the accumulation of the peptides. My research project focuses precisely on such kind of investigations. Different Cu(II) and Cu(I) chelators are studied, in the presence or not of Zn(II), in order to understand the different criteria to take into account for the development of good chelators. Different proof-of-concepts are developed in the first part. The kinetic aspect of the removal of Cu(II) from the Aß peptide by a chelator is studied with macrocyclic ligands Then, the redox state of Cu ions in the synaptic cleft staying unknown, two Cu(I) or Cu(I/II) chelators are proposed. The second part of the study takes into account the impact of Zn(II) in the Cu chelation. The thermodynamic part of the Cu(II) chelation in the presence of Zn(II) is evidenced with different chelators.
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Amandine Conte-Daban. Nouvelles preuves de concept pour la chélatothérapie contre la maladie d'Alzheimer : études spectroscopiques des interactions entre les ions cuivre et zinc. Coordination chemistry. Université Paul Sabatier - Toulouse III, 2017. English. ⟨NNT : 2017TOU30380⟩. ⟨tel-02013566⟩

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