Conformational Differences between Two Amyloid β Oligomers of Similar Size and Dissimilar Toxicity

Several protein conformational disorders (Parkinson 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. Here we report the characterization of two oligomers of the 42-residue amyloid beta (A beta 42) peptide associated with Alzheimer disease that possess similar size and dissimilar toxicity. We find that A beta 42 spontaneously forms prefibrillar oligomers at A beta concentrations below 30 mu M in the absence of agitation, whereas higher A beta concentrations lead to rapid formation of fibrils. Interestingly, A beta prefibrillar oligomers do not convert into fibrils under quiescent assembly conditions but instead convert into a second type of oligomer with size and morphology similar to those of A beta prefibrillar oligomers. Strikingly, this alternative A beta oligomer is non-toxic to mammalian cells relative to A beta monomer. We find that two hydrophobic peptide segments within A beta (residues 16-22 and 30-42) are more solvent-exposed in the more toxic A beta oligomer. The less toxic oligomer is devoid of beta-sheet structure, insoluble, and non-immunoreactive with oligomer-and fibril-specific antibodies. Moreover, the less toxic oligomer is incapable of disrupting lipid bilayers, in contrast to its more toxic oligomeric counterpart. Our results suggest that the ability of non-fibrillar A beta oligomers to interact with and disrupt cellular membranes is linked to the degree of solvent exposure of their central and C-terminal hydrophobic peptide segments.