Aggregation Dynamics of a 150 kDa Aß42 Oligomer: Insights from Cryo Electron Microscopy and Multimodal Analysis.

ABSTRACT

Protein misfolding is a widespread phenomenon that can result in the formation of protein aggregates, which are markers of various disease states, including Alzheimer's disease (AD). In AD, amyloid beta (Aß) peptides, particularly Aß40 and Aß42, are key players in the disease's progression, as they aggregate to form amyloid plaques and contribute to neuronal toxicity. Recent research has shifted attention from solely Aß fibrils to also include Aß protofibrils and oligomers as potentially critical pathogenic agents. Particularly, oligomers demonstrate greater toxicity compared to other Aß specie. Hence, there is an increased interest in studying the correlation between toxicity and their structure and aggregation pathway. The present study investigates the aggregation of a 150 kDa Aß42 oligomer that does not lead to fibril formation over time. Using negative stain transmission electron microscopy (TEM), size exclusion chromatography (SEC), dynamic light scattering (DLS), and cryo-electron microscopy (cryo-EM), we demonstrate that 150 kDa Aß42 oligomers form higher-order string-like assemblies over time. The strings are unique from the classical Aß fibril structures. The significance of our work lies in elucidating molecular behavior of a novel non-fibrillar form of Aß42 aggregate.