An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

Abstract

The deposition of amyloid in brain tissue in the context of neurodegenerative diseases involves the formation of intermediate species-termed oligomers-of lower molecular mass and with structures that deviate from those of mature amyloid fibrils. Because these oligomers are thought to be primarily responsible for the subsequent disease pathogenesis, the elucidation of their structure is of enormous interest. Nevertheless, because of the high aggregation propensity and the polydispersity of oligomeric species formed by the proteins or peptides in question, the preparation of appropriate samples for high-resolution structural methods has proven to be rather difficult. This is why theoretical approaches have been of particular importance in gaining insights into possible oligomeric structures for some time. Only recently has it been possible to achieve some progress with regard to the experimentally based structural characterization of defined oligomeric species. Here we discuss how theory and experiment are used to determine oligomer structures and what can be done to improve the integration of the two disciplines.

Coarse‐grained and All‐atom Simulations towards the Early and Late Steps of Amyloid Fibril Formation

“…The role of this contact on the early oligomers and toxicity has been discussed experimentally ,. Consistent with many models of Aβ oligomers derived from nuclear magnetic resonance (NMR) spectroscopy,, we find transient antiparallel β‐sheets between the two CHCs. Our equilibrium ensemble also reveals: short‐lived all‐α topologies (Figure A); all‐β topologies (Figure B) with two perpendicular β‐sheets; mixed αβ topologies, characterized by one compact peptide, with the β‐sheet structure stabilized by a rather extended peptide with α‐helical content; and parallel β‐sheets between the CHC and the C‐terminus, rather than between the two CHCs and between the two C‐termini, as observed in the fibrillar states.…”

Structural differences between amyloid beta oligomers

“…Structural information about amyloid oligomers is important for better understanding of their pathological roles in the disease and for development of therapeutic agents that block oligomers from propagating from cell to cell by preventing their entry into cells, dissociate their toxic secondary structures, or by inhibiting further polymerization with endogenous soluble Aβ [8,9].…”

Potential Artifacts in Sample Preparation Methods Used for Imaging Amyloid Oligomers and Protofibrils due to Surface-Mediated Fibril Formation

“…Among different types of aggregates, structured oligomers have been recognized as potentially more toxic species than other structures. 10–12 However, characterizing these small structures is still challenging, particularly due to challenges associated with proper sample preparation.…”