Emerging biophysical origins and pathogenic implications of amyloid oligomers

Introduction

The term “oligomer” refers to the association of a few monomers, per its Greek origin. In polymer chemistry, oligomers are linear, cyclic, branched, or globular molecules composed of repeating monomeric units, strung together by covalent forces or hydrogen bonds. In polymer physics, oligomers are beads on a string possessing a finite persistence length, interacting intra- and inter-molecularly via electrostatics in good or poor solvents. In biology, DNA and RNA oligonucleotides are opposing strands held together by hydrogen bonds and stabilized by π-stacking and polyelectrolytes. In all these cases, the oligomers are structurally defined, synthetically or naturally constructed to serve a specific engineering, physical, or biological purpose. But what exactly are the structure and purpose of the oligomers of amyloid proteins and peptides (“amyloid proteins” for brevity)?

Within the scope of amyloid science, oligomers denote a few to tens of monomeric amyloid proteins assembled together via nonspecific forces and hydrogen bonding, assuming globular, curvilinear, branched, or annular morphologies on the nanoscale¹external link, opens in a new tab^,2external link, opens in a new tab. Such oligomers are heterogeneous and transient in structure, and their precise roles remain vague in cell biology and medicine. Small protofibrils, formed en route to amyloid fibrils, are sometimes classified under the same envelope as oligomers³external link, opens in a new tab, possibly due to their shared features in small size and entailed toxicity.

How oligomers arise from monomers through physical forces under quasi-equilibria remains one of the most important, fascinating and yet controversial topics in amyloid protein science. The amyloid hypothesis was proposed by Hardy and Higgins⁴external link, opens in a new tab in 1992, depicting the kinetic processes of primary nucleation, elongation, and saturation of converting monomeric amyloid proteins into amyloid fibrils. This influential paradigm has since gone through major modifications to accommodate secondary nucleation⁵external link, opens in a new tab, liquid-liquid phase separation (LLPS)⁶external link, opens in a new tab, as well as cross seeding⁷external link, opens in a new tab each of which contributing to amyloid aggregation. Structurally, an amyloid protein, with the notable exception of tau, typically consists of three distinct regions: an N-terminus, a primary (and, sometimes, a secondary) amyloidogenic fragment, and a C-terminus. Environmental factors such as the cell membrane, metal ions, chaperone proteins, temperature and solvent pH also contribute to the aggregation dynamics of amyloid proteins⁸external link, opens in a new tab^,9external link, opens in a new tab. The N-terminus of amyloid-beta (Aβ), a peptide associated with the pathology of Alzheimer’s disease (AD), can initiate association of the peptide with the cell membrane to trigger structural transitions towards β-sheet rich oligomers and cross-β fibrils⁸external link, opens in a new tab. The C-terminus of Aβ₄₂, on the other hand, enhances the amyloidogenic potential of the peptide¹⁰external link, opens in a new tab. As the concentration of amyloid proteins rises above a threshold, prompted by pathophysiological conditions or environmental triggers, amyloid proteins sample through a host of conformations along the free-energy landscape, transforming from monomeric to oligomeric, protofibrillar and fibrillar states driven by thermodynamics, as observed time and again in vitro and in vivo. In this article, we focus on the LLPS process and the monomer to β-barrel evolution in oligomer formation (Fig. 1external link, opens in a new tab), as primary and secondary nucleation in amyloidosis have been extensively reviewed elsewhere¹external link, opens in a new tab^,11external link, opens in a new tab^,12external link, opens in a new tab.