(157g) Conformational Differences Between Toxic and Non-Toxic Oligomers of Amyloid ß

Many amyloidogenic proteins misfold into soluble oligomers that mature into amyloid fibrils. In addition to this pathway, we have discovered that soluble oligomers of the amyloid β (Aβ) peptide associated with Alzheimer’s disease can mature into a second oligomeric isoform of identical size that possesses a combination of biochemical properties distinct from highly toxic Aβ soluble oligomers and mildly toxic fibrils. Importantly, these uniquely folded Aβ oligomers are non-toxic to mammalian cells. In this presentation, we will discuss our characterization of Aβ soluble and non-toxic oligomers using a panel of biochemical, immunological, imaging and cell toxicity assays. Importantly, we find that the lack of toxicity for Aβ non-toxic oligomers relative to soluble oligomers and fibrils is not due to simple differences in size, secondary structure, hydrophobicity and conformational stability. We will discuss our recent site-specific analysis of Aβ soluble and non-toxic oligomers aimed at identifying the size-independent conformational determinants of Aβ-mediated toxicity.