Spatial propagation of protein polymerization.

We consider the spatial dependence of filamentous protein self-assembly. Through studying the cases where the spreading of aggregated material is dominated either by diffusion or by growth, we derive analytical results for the spatial evolution of filamentous protein aggregation, which we validate against Monte Carlo simulations. Moreover, we compare the predictions of our theory with experimental measurements of two systems for which we identify the propagation as either growth or diffusion controlled. Our results connect the macroscopic observables that characterize the spatial propagation of protein self-assembly with the underlying microscopic processes and provide physical limits on spatial propagation and prionlike behavior associated with protein aggregation.

Pyroglutamate-modified Aß(3-42) affects aggregation kinetics of Aß(1-42) by accelerating primary and secondary pathways.

The aggregation into amyloid fibrils of amyloid-ß (Aß) peptides is a hallmark of Alzheimer's disease. A variety of Aß peptides have been discovered in vivo, with pyroglutamate-modified Aß (pEAß) forming a significant proportion. pEAß is mainly localized in the core of plaques, suggesting a possible role in inducing and facilitating Aß oligomerization and accumulation. Despite this potential importance, the aggregation mechanism of pEAß and its influence on the aggregation kinetics of other Aß variants have not yet been elucidated. Here we show that pEAß(3-42) forms fibrils much faster than Aß(1-42) and the critical concentration above which aggregation was observed was drastically decreased by one order of magnitude compared to Aß(1-42). We elucidated the co-aggregation mechanism of Aß(1-42) with pEAß(3-42). At concentrations at which both species do not aggregate as homofibrils, mixtures of pEAß(3-42) and Aß(1-42) aggregate, suggesting the formation of mixed nuclei. We show that the presence of pEAß(3-42) monomers increases the rate of primary nucleation of Aß(1-42) and that fibrils of pEAß(3-42) serve as highly efficient templates for elongation and catalytic surfaces for secondary nucleation of Aß(1-42). On the other hand, the addition of Aß(1-42) monomers drastically decelerates the primary and secondary nucleation of pEAß(3-42) while not altering the pEAß(3-42) elongation rate. In addition, even moderate concentrations of fibrillar Aß(1-42) prevent pEAß(3-42) aggregation, likely due to non-reactive binding of pEAß(3-42) monomers to the surfaces of Aß(1-42) fibrils. Thus, pEAß(3-42) accelerates aggregation of Aß(1-42) by affecting all individual reaction steps of the aggregation process while Aß(1-42) dramatically slows down the primary and secondary nucleation of pEAß(3-42).