LAUSR

Soluble oligomers of the amyloid-β (Aβ) peptide have emerged as the primary neurotoxic agents in Alzheimer disease (AD). Increasing evidence implicates aggregates of Aβ to propagate towards fibrils in a strain-specific manner. Morphological differences observed within fibrils are known to arise due to micro-structural differences among the smaller aggregates that form the fibril building blocks. Furthermore, polymorphic fibrils correlate with the clinically observed phenotypes in AD pathology, cementing the idea that conformational strains of oligomers may have significance in phenotypic outcomes. Given the existing diversity among Aβ oligomers, it becomes imperative to determine the ability of various oligomeric strains to faithfully propagate their structure. However, dearth in a molecular understanding of Aβ oligomers has confounded the insights into such a mechanism. We have previously established that a distinct dodecamer of Aβ42, called large fatty acid-derived oligomers (LFAOs), are formed as an off-pathway species under interfacial conditions. Here we demonstrate that at high concentrations, LFAOs seed Aβ towards fibrils containing distinct morphological features different from those generated in the absence of the seed. More importantly, the fibril structure seems to contain units of parent LFAO seeds, indicating a biophysically faithful propagation of the seed. The observations reported here may have profound significance in deciphering the emerging roles of Aβ oligomer phenotypes in prion-like propagation and dissemination of toxicity in AD.