Amide solvent protection analysis demonstrate that amyloid-{beta}(1-40) and amyloid-{beta}(1-42) form different fibrillar structures under identical conditions
Résumé
Alzheimer‘s disease (AD) is a neurodegenerative disorder characterized by self-assembly and amyloid formation of the 39-43 residue long Amyloid-β (Aβ) peptide. The most abundant species, Aβ(1-40) and Aβ(1-42), are both present within senile plaques, but Aβ(1-42) peptides are considerably more prone to self-aggregation and are also essential for the development of AD. To understand the molecular and pathological mechanisms behind AD, a detailed knowledge of the amyloid structures of Aβ-peptides is vital. In the present work we have used quenched hydrogen/deuterium exchange NMR experiments to probe the structure of Aβ(1-40) fibrils. The fibrils were prepared and analyzed identically as in our previous study on Aβ(1-42) fibrils, allowing a direct comparison of the two fibrillar structures. The solvent protection pattern of Aβ(1-40) fibrils revealed two well protected regions, consistent with a structural arrangement of two β-strands connected with a bend. This protection pattern partly resembles the pattern found in Aβ(1-42) fibrils, but the Aβ(1-40) fibrils display a significantly increased protection for the N-terminal residues Phe4-His14, suggesting that additional secondary structure is formed in this region. In contrast, the C-terminal residues Gly37-Val40 show a reduced protection that suggests a loss of secondary structure in this region and an altered filament assembly. The differences between our study and other similar investigations suggest that subtle variations in fibril-preparation conditions may significantly affect the fibrillar architecture.
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