Distinct Primary Nucleation of Polymorphic Aβ Dimers Yields to Distinguished Fibrillation Pathways

Polymorphic Aβ dimers are the smallest toxic species that play a role in the pathology of Alzheimer's disease. There is great interest in understanding the malfunctions that yield to these toxic species and in providing insights into the molecular mechanisms of the primary nucleation. Herein, we present a first work that demonstrates two distant edges states of Aβ dimers. The first is the so-called "random coil" state dimer that mimics the primary seeding/nucleation that is far from a fibrillation state. The second is the "fibril-like" state dimer that is structurally in close proximity to the fibril, a well-organized state into a fibril-like structure. We show for the first time that a conformational change of one monomer within the dimer impedes primary nucleation, while less fluctuations and relatively large number of interactions in nucleation domains induce the primary nucleation to produce toxic stable species. Overall, the current study exhibits a diversity of primary nucleation in each dimer state, suggesting distinct molecular mechanisms of fibril formation. The conformations of the early stage Aβ dimers that were achieved may provide crucial data for designing inhibitors to impede the primary nucleation.