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Rôle de la région N-terminale 1-16 du peptide amyloïde Abeta dans la deposition amyloïde associée à la maladie d'Alzheimer : Plasticité conformationnelle, modifications liées au vieillissement protéique et interaction avec les ions Zn2+

Abstract : Amyloid deposits are extracellular fibrillar lesions associated with Alzheimer's disease that are mainly composed of the amyloid peptide, Aβ. The transition of Aβ helical or random secondary structure towards a β-sheet conformation, with concomitant peptide fibrillization, is a proposed mechanism of plaque formation. Amyloid deposits contain a high content of zinc ions, and display an important heterogeneity of the N-terminal part of Aβ, with troncated, isomerized and racemized forms. These modifications as well as the interaction with Zn2+ have been suggested to take part in Aβ fibrillogenesis, or to occur after the amyloid deposition, given the accessibility of the N-terminal region of Aβ within amyloid fibrils.
Our study was mainly focused on the 1-16 N-terminal region of Aβ, Aβ(1-16), which is suggested to be implicated in Zn2+ binding and displays several sites that are able to undergo protein-aging related modifications. Our aim was to characterize the different molecular mechanisms which alter Aβ and could inhibit the recognition of this potential therapeutic target, by anti-Aβ antibodies in particular.
We showed by circular dichroism (CD) and NMR spectroscopy the conformational plasticity of Aβ(1-16), and characterized the structures displayed by the peptide in aqueous medium and in membrane-mimicking medium. Furthermore, we examined the in vitro aging of Aβ(1-16) and identified the modified peptides. The Aβ(1-16)/Zn2+ complex was studied by CD, NMR and ESI-MS, allowing to propose a model for zinc binding to Aβ(1-16). Aβ(1-16) binds to zinc in a tetrahedral geometry, with H6, E11, H13 et H14 as zinc ligands. Furthermore, we showed that this binding modifies the in vitro aging profile of Aβ(1-16) and induces an agonist effect on the recognition of this region of Aβ by cognate antibodies. Two of the modified peptides produced upon in vitro aging, Aβ(1-16)-L-IsoAsp7 and Aβ(1-16)-D-Asp7, were characterized by NMR, illustrating a local change of the conformation in the H6-S8 region, as compared to Aβ(1-16), but no major conformational rearrangement. Zn2+ binding to Aβ(1-16)-L-IsoAsp7 appears to result from a different coordination motif, the IsoAsp residue being involved.
Finally, a complementary investigation undertaken on Aβ(1-40) indicates that the presence of Zn2+ or of anti-Aβ antibodies raised against the N-terminal part of Aβ prevents Aβ fibrillogenesis and rather leads to the production of different types of aggregates. Our results suggest that the above mentioned interactions between the 1-16 N-terminal region of Aβ and either Zn2+ or anti-Aβ antibodies inhibit the fibrillogenesis of the full-length amyloid peptide.
Complete list of metadatas

https://tel.archives-ouvertes.fr/tel-00170474
Contributor : Séverine Zirah <>
Submitted on : Friday, September 7, 2007 - 10:44:03 PM
Last modification on : Monday, December 14, 2020 - 9:55:29 AM
Long-term archiving on: : Thursday, April 8, 2010 - 7:36:30 PM

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  • HAL Id : tel-00170474, version 1

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Séverine Zirah. Rôle de la région N-terminale 1-16 du peptide amyloïde Abeta dans la deposition amyloïde associée à la maladie d'Alzheimer : Plasticité conformationnelle, modifications liées au vieillissement protéique et interaction avec les ions Zn2+. Autre. Université Pierre et Marie Curie - Paris VI, 2004. Français. ⟨tel-00170474⟩

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