Amide solvent protection analysis demonstrates that amyloid-beta(1-40) and amyloid-beta(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 Abeta (amyloid-beta)-peptide. The most abundant species, Abeta(1-40) and Abeta(1-42), are both present within senile plaques, but Abeta(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 Abeta-peptides is vital. In the present study we have used quenched hydrogen/deuterium-exchange NMR experiments to probe the structure of Abeta(1-40) fibrils. The fibrils were prepared and analysed identically as in our previous study on Abeta(1-42) fibrils, allowing a direct comparison of the two fibrillar structures. The solvent protection pattern of Abeta(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 Abeta(1-42) fibrils, but the Abeta(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 the present study and other similar investigations suggest that subtle variations in fibril-preparation conditions may significantly affect the fibrillar architecture.
Olofsson
Anders
A
Umeå Centre for Molecular Pathogenesis, Umeå University, SE-901 87 Umeå, Sweden. anders.olofsson@ucmp.umu.se
Lindhagen-Persson
Malin
M
Sauer-Eriksson
A Elisabeth
AE
Ohman
Anders
A
D000544:Alzheimer Disease / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D016874:Neurofibrillary Tangles / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D012996:Solutions; D012997:Solvents
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012996:Solutions; D012997:Solvents; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)