The conformational stability of nonfibrillar amyloid-β peptide oligomers critically depends on the C-terminal peptide length.

The amyloid-β (Aβ) peptide is one key molecule in the pathogenesis of Alzheimer's disease. We investigated the conformational stability of a nonfibrillar tetrameric Aβ structure by molecular dynamics (MD) simulations revealing that the stability of the Aβ tetramer depends critically on the C-terminal length. In contrast to the Aβ17-40 tetramer, which proved to be instable, the simulations demonstrate structural integrity of the Aβ17-42 and Aβ17-43 tetramers. These differences in stability can be attributed to an extension of the middle strand of a three-stranded antiparallel β sheet through residues 41-43, only present in the longer Aβ species that aggregate faster and are more neurotoxic. Additional MD simulations demonstrate that this higher stability is also present in the monomers forming the tetramer. In conclusion, our findings suggest the existence of a nonfibrillar oligomer topology that is significantly more stable for the longer Aβ species, thus offering a structural explanation for their higher neurotoxicity.