Conformational Differences Between Beta-Amyloid Oligomers of Similar Size and Dissimilar Toxicity

Several protein conformational disorders (Parkinson’s and prion diseases) are linked to aberrant folding of proteins into prefibrillar oligomers and amyloid fibrils. Although prefibrillar oligomers are more toxic than their fibrillar counterparts, it is difficult to decouple the origin of their dissimilar toxicity because oligomers and fibrils differ both in terms of structure and size. We have discovered that the 42-residue beta-amyloid peptide associated with Alzheimer’s disease spontaneously assembles into two prefibrillar oligomers with similar size and dissimilar toxicity (Ladiwala et al., JBC, 2012). In this presentation, we will discuss our characterization of beta-amyloid oligomers using conventional and novel site-specific structural methods. We find that hydrophobic regions within beta-amyloid oligomers are more solvent exposed in the more toxic oligomer. Moreover, the more toxic oligomer disrupts lipid bilayers, while the less toxic oligomer is inactive. Our results suggest that the ability of beta-amyloid oligomers to interact with and disrupt cellular membranes is linked to the degree of solvent exposure of their hydrophobic residues.