Amide solvent protection analysis demonstrates that amyloid-β(1–40) and amyloid-β(1–42) form different fibrillar structures under identical conditions

AD (Alzheimer’s disease) is a neurodegenerative disorder characterized by self-assembly and amyloid formation of the 39–43 residue long Aβ (amyloid-β)-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 selfaggregation 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 Aβpeptides is vital. In the present study we have used quenched hydrogen/deuterium-exchange NMR experiments to probe the structure of Aβ(1–40) fibrils. The fibrils were prepared and analysed 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 wellprotected 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 Phe–His, suggesting that additional secondary structure is formed in this region. In contrast, the C-terminal residues Gly–Val show a reduced protection that suggests a loss of secondary structure in this region and an altered filament assembly. The differences between the present study and other similar investigations suggest that subtle variations in fibril-preparation conditions may significantly affect the fibrillar architecture.