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The aggregation pathways of A beta 42 peptides are complex and can lead to both amyloids and nonamyloid aggregates. We use in situ atomic force microscopy imaging to monitor the assembly of aggregate structures and their dynamics. Two aggregation pathways emerge, one leading to amyloid fibrils and a second one that includes the formation of oligomers and apparently amorphous aggregates, which we identify as nonamyloid. Whereas the fibrils seem to require elevated peptide concentration to nucleate and grow, oligomers and amorphous aggregates form at near-physiological peptide concentrations. On the time scales of the experiments, the two aggregation pathways do not cross: the oligomers and aggregates do not participate in the fibrillization pathway and, analogously, secondary nucleation assisted by mature fibrils does not produce misfolded aggregates. We show that distinct A beta 42 fibril polymorphs form and coexist under identical conditions. Mature fibrils serve as substrates for secondary nucleation that leads to forked, branched, and thicker fibrils and, importantly, produces new fibril fragments. A beta 42 fibrils accumulate structural defects, with more defects generated at higher peptide concentrations. The defects lead to substantial variations of growth rate both over time and between different fibrils. The average growth rates of A beta 42 fibrils are about 50-fold faster than those of A beta 40 fibrils. Our findings are consistent with the basic premise of the polymorph selection hypothesis, according to which the late onset of Alzheimer's disease, its high clinical variability, and the presence of amyloid plaques in healthy individuals have their origins in differing toxicities and aggregation kinetics of distinct A beta structural polymorphs. 

A fundamental assumption of the classical theories of crystal nucleation is that the individual molecules from the “old” phase associate to an emerging nucleus individually and sequentially. 

Abstract Hematin crystallization is an essential element of heme detoxification of malaria parasites and its inhibition by antimalarial drugs is a common treatment avenue. We demonstrate at biomimetic conditions in vitro irreversible inhibition of hematin crystal growth due to distinct cooperative mechanisms that activate at high crystallization driving forces. The evolution of crystal shape after limited-time exposure to both artemisinin metabolites and quinoline-class antimalarials indicates that crystal growth remains suppressed after the artemisinin metabolites and the drugs are purged from the solution. Treating malaria parasites with the same agents reveals that three- and six-hour inhibitor pulses inhibit parasite growth with efficacy comparable to that of inhibitor exposure during the entire parasite lifetime. Time-resolved in situ atomic force microscopy (AFM), complemented by light scattering, reveals two molecular-level mechanisms of inhibitor action that prevent β-hematin growth recovery. Hematin adducts of artemisinins incite copious nucleation of nonextendable nanocrystals, which incorporate into larger growing crystals, whereas pyronaridine, a quinoline-class drug, promotes step bunches, which evolve to engender abundant dislocations. Both incorporated crystals and dislocations are known to induce lattice strain, which persists and permanently impedes crystal growth. Nucleation, step bunching, and other cooperative behaviors can be amplified or curtailed as means to control crystal sizes, size distributions, aspect ratios, and other properties essential for numerous fields that rely on crystalline materials.