Probing the conformational dynamics of amyloid oligomers in biologically relevant microenvironments

Abstract

Amyloidogenic peptides, classified for their propensity to form fibrillar cross-β structures, are both physiologically functional and implicated in the development of diseases, such as Alzheimer's disease (AD). It is generally accepted that metastable oligomers are the principal cytotoxic species, which permeabilize plasma membranes and induce Ca2+ dysregulation. In the 25 years since the introduction of the oligomer hypothesis, the phenomenon remains poorly understood. While some amyloids are cytotoxic, others do not spontaneously aggregate in ways related to disease progression. Despite all amyloids sharing a propensity to form fibrils, the biophysical properties underpinning this distinction remain unclear. Additionally, the influence of the aggregation microenvironment on amyloid conformational dynamics remains a large confounding factor in our understanding of oligomeric species. Amyloidogenic peptides are typically intrinsically disordered, and their conformational landscape is highly sensitive to aggregation conditions, like the presence of co-aggregates or membrane composition. The work presented here utilizes molecular dynamics (MD) simulation to probe the structure and dynamics of amyloid oligomerization. Specifically, we examine the amyloidogenic properties of amyloid-β (Aβ), the peptide central to AD pathogenesis, and β-endorphin (βE), a non-toxic signaling amyloid, to identify properties associated with aberrant aggregation events. Additionally, we examine the role of amyloid cross-seeding to better understand synergies between different amyloid-related disease states. Finally, we examine the influence of lipids, both as co-aggregates and in model neuronal membrane, to elucidate their role in modulating Aβ oligomer dynamics. Our findings emphasize the role of Aβ hydrophobic sequences in mediating oligomerization events, including self-association, cross-seeding and lipid interactions. This work provides a rationale for the future development of therapeutics to disrupt the formation of cytotoxic amyloid oligomers.