Assembly of Aβ proceeds via monomeric nuclei.

Aggregation of amyloid-β (Aβ) peptides is fundamental to Alzheimer's disease. It has now been shown that nucleated proliferation of Aβ fibrils utilizes a secondary mechanism with existing fibrils catalyzing the formation of new ones. Here it is shown that the data for Aβ40 and Aβ42 require that the nuclei be monomeric; that is, an initial, unfavorable conformational change is rate limiting for the processes that appear to be nucleation. Following the conformational change, the assembly process is "downhill" despite clear lag times and significant concentration dependence. The similarity to polyglutamine nucleation suggests that monomeric nuclei may be widespread in amyloid formation.