The basic structural motif and major biophysical properties of Amyloid-β are encoded in the fragment 18–35

Abstract

Aggregation and misfolding of the amyloid beta (Aβ) peptide is thought to initiate Alzheimer’s disease (AD). Here we study the role played by its central segment (Aβ_18–35) in determining these properties. Aβ_18–35 has a solubility of 18 μM. The soluble fraction consists mainly of small oligomers, which have mixed β-sheet and random coil structures. The monomer is mostly a random coil with some residual compactness. Aggregated Aβ_18–35 forms fibrils of width 3.0 ± 0.7 nm, which is consistent with a hairpin shape. Each of these properties has a close similarity to Aβ₄₀. Remarkably, solid state NMR indicates that the fibrils also retain the secondary structure and tertiary contacts of Aβ₄₀. This is the shortest fragment of Aβ reported so far which preserves its fibrillar architecture, including the hairpin turn, as well as its solution phase conformational properties. Residues 18–35 should therefore be a key target of AD therapeutics.