ABSTRACT
Amyloid-ß oligomers (AßOs) self-assemble into polymorphic species with diverse biological activities that are implicated causally to Alzheimer's disease (AD). Synaptotoxicity of AßO species is dependent on their quaternary structure, however, low-abundance and environmental sensitivity of AßOs in vivo have impeded a thorough assessment of structure-function relationships. We developed a simple biochemical assay to quantify the relative abundance and morphology of cross-linked AßOs. We compared oligomers derived from synthetic Aß40 (wild-type (WT) Aß40) and a recombinant source, called Aß(M1-40). Both peptides assemble into oligomers with common sizes and morphology, however, the predominant quaternary structures of Aß(M1-40) oligomeric states were more diverse in terms of dispersity and morphology. We identified self-assembly conditions that stabilize high-molecular weight oligomers of Aß(M1-40) with apparent molecular weights greater than 36 kDa. Given that mixtures of AßOs derived from both peptides have been shown to be potent neurotoxins that disrupt long-term potentiation, we anticipate that the diverse quaternary structures reported for Aß(M1-40) oligomers using the assays reported here will facilitate research efforts aimed at isolating and identifying common toxic species that contribute to synaptic dysfunction.
