Secondary nucleation in amyloid formation

Abstract

Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates. A key question in current research is the molecular mechanism and driving forces governing such processes, known as secondary nucleation. In this context, the analogies with other self-assembling systems for which monomer-dependent secondary nucleation has been studied for more than a century provide a valuable source of inspiration. Here, we present a short overview of this background and then review recent results regarding secondary nucleation of amyloid-forming peptides and proteins, focusing in particular on the amyloid β peptide (Aβ) from Alzheimer's disease, with some examples regarding α-synuclein from Parkinson's disease. Monomer-dependent secondary nucleation of Aβ was discovered using a combination of kinetic experiments, global analysis, seeding experiments and selective isotope-enrichment, which pinpoint the monomer as the origin of new aggregates in a fibril-catalyzed reaction. Insights into driving forces are gained from variations of solution conditions, temperature and peptide sequence. Selective inhibition of secondary nucleation is explored as an effective means to limit oligomer production and toxicity. We also review experiments aimed at finding interaction partners of oligomers generated by secondary nucleation in an ongoing aggregation process. At the end of this feature article we bring forward outstanding questions and testable mechanistic hypotheses regarding monomer-dependent secondary nucleation in amyloid formation.

β‐Amyloid aggregation and heterogeneous nucleation

“…An additional important phenomenon in fibril growth is secondary nucleation (which could also have been considered as a special example of heterogeneous nucleation). In secondary nucleation, new nucleation sites arise on preexisting aggregates made of the same type of monomeric units (e.g., Aβ molecules) . Though clearly important in the overall kinetics of fibrillization, we will not discuss this further as this occurs after a fibril has already formed.…”

“…In secondary nucleation, new nucleation sites arise on preexisting aggregates made of the same type of monomeric units (e.g., Aβ molecules). 10 Though clearly important in the overall kinetics of fibrillization, we will not discuss this further as this occurs after a fibril has already formed. The aggregation of Aβ peptides is quite complex, but we confine ourselves to one particular aspect of it: the possibility of heterogeneous nucleation as a factor catalyzing soluble oligomer and fibril formation.…”

“…155 (c) Rat-Aβ(1-16) dimer (Zn 2+ ); pdb 2li9. The rat Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) peptide also binds Zn 2+ and other metal ions, despite lacking the His13 residue of human Aβ chemical shifts), while in mature fibrils, these residues extend the N-terminal β-strand segment.…”

Mathematical model shows how sleep may affect amyloid β fibrillization

“…Although the amyloid aggregation is still an active field of research, there is a consensus that such a phenomenon occurs through these two mechanisms. The secondary nucleation has been understood as the leading mechanism for amyloid plaque formation in AD [48,49,50].…”

Fluorescence Detection and Dissociation of Amyloid‐β Species for the Treatment of Alzheimer's Disease

“…Knowles and Linse reported the molecular chaperone Brichos [141] (a protein containing about 100 amino acid residues) to inhibit Aβ aggregation through the inhibition of Aβ secondary nucleation [142,143] by binding to fibril surfaces. Knowles and Linse reported the molecular chaperone Brichos [141] (a protein containing about 100 amino acid residues) to inhibit Aβ aggregation through the inhibition of Aβ secondary nucleation [142,143] by binding to fibril surfaces.…”