Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils

Abstract

Amyloid Diseases involve the growth of disease specific proteins into amyloid fibrils and their deposition in protein plaques. Amyloid fibril formation is typically preceded by oligomeric intermediates. Despite significant efforts, the specific role fibrils or oligomers play in the etiology of any given amyloid disease remains controversial. In neurodegenerative disease, though, amyloid oligomers are widely considered critical contributors to disease symptoms. Aside from oligomers as inevitable on-pathway precursors of fibril formation, there is significant evidence for off-pathway oligomer formation competing with fibril growth. The distinct mechanisms and pathways of oligomer formation directly affect our understanding under which conditions oligomers emerge in vivo, and whether their formation is directly coupled to, or distinct from, amyloid fibril formation. In this review, we will discuss the basic energy landscapes underlying the formation of on-pathway vs. off-pathway oligomers, their relation to the related amyloid aggregation kinetics, and their resulting implications for disease etiology. We will review evidence on how differences in the local environment of amyloid assembly can dramatically shift the relative preponderance of oligomers vs. fibrils. Finally, we will comment on gaps in our knowledge of oligomer assembly, of their structure, and on how to assess their relevance to disease etiology.

Conformation of Pyroglutamated Amyloid β (3–40) and (11–40) Fibrils – Extended or Hairpin?

“…The situation for pE 3 -AMPP-Aβ 3–40 is a bit different compared with the other two variants. The biphasic ThT fibrillation curve (Figure ) resembles metastable oligomers, which are confirmed with CV measurements. ,− …”

“…The biphasic ThT fibrillation curve ( Figure 5 ) resembles metastable oligomers, which are confirmed with CV measurements. 39 , 50 − 52 …”

Real-time monitoring of the amyloid β1–42 monomer-to-oligomer channel transition using a lipid bilayer system

“…They are expected to have very short lifetimes, and the populations are inherently limited. To date, although ThT and AFM experiments have used alternate approaches to monitor the kinetics or dynamics of oligomerization, it has remained a challenge ( 42 , 43 ). Several studies have reported the channel current measurement of Aβ42 using a planar lipid bilayer, which is formed with the Montal–Mueller or painting methods ( 15 , 25 ).…”

Peptide Self-Assembly into Amyloid Fibrils: Unbiased All-Atom Simulations

“…16 For short peptides, Eisenberg and Sawaya 15 identified six and four symmetry classes that emerge from packing of parallel or antiparallel β-sheets against each other, respectively, see Figure 1c Amyloid peptides require a minimum critical concentration to form fibrils, and there is evidence that disordered globular aggregates emerge at high concentrations without nucleating fibrils within experimental time scales. 18,19 This upper bound concentration is dependent on the peptide sequence and is on the order of a few millimolar for the long Aβ peptide, whereas it may be much higher or lower for short peptides. This is relevant for computational studies since all-atom simulations cannot track the motion of more than a few millions of atoms for a few microseconds using state-of-the-art resources.…”

“…Nowadays, it is mostly accepted that the formation of amyloid fibrils emanates from the general properties of the polypeptide backbone . Thus, any peptide sequence is expected to form fibrils under the appropriate conditions, although off-pathway oligomers have also been reported. , However, the propensity of a peptide to form fibrils depends enormously on its amino acid sequence. The latter determines the secondary structure of peptides and their ability to segregate nonpolar and polar residues when incorporated onto amyloid fibrils.…”