Thomas Michaels — Harvard University e Cambridge University #
Mechanisms of amyloid self-assembly from kinetic analysis #
Amyloid aggregation is a process in which dispersed proteins and peptides assemble spontaneously to form ordered elongated structures. This phenomenon is an essential characteristic of life but is also at the heart of pathologies of many types, including Parkinson’s and Alzheimer’s diseases. To curtail amyloid assembly for medical purposes it is necessary to quantify the fundamental principles that control the way dispersed molecules assemble into these ordered structures. The fundamental challenge in establishing such an understanding in a rigorous manner is the disparate nature of the spatial and temporal scales involved, which range from the molecular to the organism scale. In this talk, I demonstrate how this challenge can be addressed by bringing the power of physical methods to amyloid aggregation to connect microscopic mechanisms with macroscopic observations of such phenomena. I discuss a unified theory of the kinetics of amyloid assembly and show how these results reveal simple rate laws that provide the basis for interpreting experimental data in terms of specific mechanisms controlling the proliferation of amyloid fibrils. I then demonstrate the power of this approach by presenting a full kinetic analysis of cytotoxic oligomer populations formed during the aggregation of the amyloid-β 1-42 (Aβ42) peptide of Alzheimer’s disease. Specifically, this analysis shows that Aβ42 oligomers are not able to undergo elongation processes to grow into fibrillar morphologies characteristic of mature amyloid fibrils, but that a rare structural transition exists which converts oligomers into growth-competent fibrils. Moreover, this strategy reveals that even through all mature amyloid fibrils originate as oligomers, the majority of oligomers dissociate into monomeric peptides before the conversion step has taken place. These results illuminate in molecular detail the mechanistic steps of amyloid formation, suggesting potential targets for intervention against neurodegenerative diseases.