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 A beta (amyloid-)-peptide. The most abundant species, A beta(1-40) and A beta(1-42), are both present within senile plaques, but A beta(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 A beta-peptides is vital. In the present study we have used quenched hydrogen/deuterium-exchange NMR experiments to probe the structure of A beta(1-40) fibrils. The fibrils were prepared and analysed identically as in our previous study on A beta(1-42) fibrils, allowing a direct comparison of the two fibrillar structures. The solvent protection pattern of A beta(1-40) fibrils revealed two well-protected regions, consistent with a structural arrangement of two beta-strands connected with a bend. This protection pattern partly resembles the pattern found in A beta (1-42) fibrils, but the A beta(1-40) fibrils display a significantly increased protection for the N-terminal residues Phe(4)-His(14) , suggesting that additional secondary structure is formed in this region. In contrast, the C-terminal residues Gly(37)-Val(40) 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.