FIGURE 8.

Schematic diagram depicting generation of off-pathway oligomers and replication. A, the classic on-pathway fibril formation process is depicted along with an alternative off-pathway. The process of replication undergone by off-pathway oligomers is shown in dotted lines. B, the aggregation process is shown as a thermodynamic funnel for intrinsically disordered proteins such as Aβ toward fibril formation. This path is considered to be the nucleation-dependant on-pathway. The spherical and oval balls represent LMW oligomers. However, the oligomers may adopt a different pathway such that they are trapped in local energy minima as off-pathway species (oval balls; gray area of the funnel). Such off-pathway species would have a significant energy barrier to overcome to proceed toward fibrils. Also, the off-pathway oligomers can recruit more monomers, which dictates them to adopt such alternate pathways (replication process shown in A). This may further increase the energy barrier for replicated off-pathway oligomers to overcome while significantly increasing their half-lives.