Ultrafast propagation of β-amyloid fibrils in oligomeric cloud

Abstract

Interaction between monomer peptides and seeds is essential for clarifying the fibrillation mechanism of amyloid β (Aβ) peptides. We monitored the deposition reaction of Aβ1–40 peptides on immobilized seeds grown from Aβ1–42, which caused formation of oligomers in the early stage. The deposition reaction and fibrillation procedure were monitored throughout by novel total-internal-reflection-fluorescence microscopy with a quartz-crystal microbalance (TIRFM-QCM) system. This system allows simultaneous evaluation of the amount of deposited peptides on the surface seeds by QCM and fibril nucleation and elongation by TIRFM. Most fibrils reached other nuclei, forming the fibril network across the nucleus hubs in a short time. We found a fibril-elongation rate two-orders-of-magnitude higher in an oligomeric cloud than reported values, indicating ultrafast transition of oligomers into fibrils.

The growth of amyloid fibrils: rates and mechanisms

“…Indeed, the thermodynamics of monomer binding to the fibril surface defines the thermodynamics of the overall secondary nucleation behaviour [62,63]. Re-evaluation of previously published data [19][20][21] within this framework shows that the reported behaviour (scaling of reversible amplitude with incubation time and monomer concentration) is consistent with the picture that upon contact between fibrils and monomer solutions, a rapid pseudo-equilibrium is established between free monomer and monomer weakly associated with binding sites on the fibril surface, which is also consistent with recent QCM experiments [64,65]. The shorter the incubation period with monomer solution, the greater the bias towards (weak, readily reversible) surface attachment and the longer the incubation time, the greater the bias towards (less reversible) elongation ( Figure 4).…”

“…The existence of multiple distinct populations of fibrils in a given sample has also been demonstrated unambiguously with the help of cryo-EM [5,6]. Inspection of Figure 5 reveals that the range of measured rate constants of amyloid fibril elongation spans approximately five orders of magnitude (not considering one single particle measurement reporting two orders of magnitude faster rates than any other experiment [65], the inclusion of which leads to a range of more than seven orders of magnitude). In this context, it is interesting to consider the theoretical upper limit of the rate constant of protein polymer growth, which is given by the diffusional arrival of monomeric protein at the polymer end.…”

In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum

“…However, the areas spatially distant from (posterior cingulate and inferior parietal cortices), but anatomically and functionally connected with those medial temporal regions were subsequently involved instead of spreading to neighboring areas. Extracellular amyloid fibrils may propagate by simple diffusion to spatially neighboring areas, [36][37][38] through the neuronal networks, 39,40 or through the blood stream. [30][31][32] After spreading through the remaining association cortices, tau accumulation finally reaches the primary cortical areas most distant from the medial temporal regions in terms of anatomical connection.…”

A glass menagerie of low complexity sequences

“…The formation of amyloid from dynamic oligomeric precursors was first reported for a low complexity prion-forming protein [29] and is now extensively documented for a multitude of other amyloid-forming proteins in vitro [10]. Once nucleation has occurred, polymerization can proceed extremely rapidly within a dynamic liquid phase due to the templated conformational conversion of other molecules in the droplet [29,30]. …”