Biophysical understanding of novel synthetic amyloid-beta (Abeta) prions in Alzheimer's disease
Oligomers of amyloid-β (Aβ) peptide are the primary toxic agents that play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Oligomers are the intermediates formed during the Aβ aggregation process leading up to insoluble fibrils. It is important to know that oligomers can also be formed via pathways that do not lead to fibril formation. Such 'off-pathway' oligomers would have significantly longer half-lives than the 'on-pathway' ones, which may result in prolonged toxicity to neuronal cells. Furthermore, neither the mechanism of neurotoxicity nor the potential mechanisms of propagation and proliferation to neighboring cells are well understood. Moreover, recent in vivo studies on transgenic animal models have implicated a prion-like mechanism involved in the propagation of toxic oligomeric seeds. Interfaces generated by lipids, fatty acids and other surfactants are well known to affect A aggregation, especially in inducing alternate pathways. In this study, the effect of saturated non-esterified fatty acids (NEFAs) on the rate of A aggregation was studied. We have observed that NEFAs were able to induce an alternate pathway of aggregation, which was depended on NEFA concentrations. More importantly, in a narrow concentration range, NEFAs induced the formation of 12-18mers (Large Fatty Acid-derived Oligomers; LFAOs), which were isolable by size exclusion chromatography (SEC). We discovered that LFAOs can behave like prions, undergoing self-propagation, by quantitatively converting monomeric Aâ into toxic LFAO assemblies in a template-assisted manner. We further analyzed the prion-like behavior of LFAOs by the 'protein misfolding via cyclic amplification' (PMCA) assay, as was done for prions. Together, our findings indicate that LFAOs are unique Aβ prions and support the developing hypothesis that a common, prion-type mechanism of infectivity could be an underlying conserved mechanism among many neurodegenerative diseases.