Michaels, TCT; Dear, AJ; Cohen, S; Vendruscolo, M; Knowles, TPJ; (2022) Kinetic profiling of therapeutic strategies for inhibiting the formation of amyloid oligomers. The Journal of Chemical Physics 10.1063/5.0077609. (In press).

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Abstract

Protein self-assembly into amyloid fibrils underlies several neurodegenerative conditions, including Alzheimer's and Parkinson's diseases. It has become apparent that the small oligomers formed during this process constitute neurotoxic molecular species associated with amyloid aggregation. Targeting the formation of oligomers represents therefore a possible therapeutic avenue to combat these diseases. However, it remains challenging to establish which microscopic steps should be targeted to suppress most effectively the generation of oligomeric aggregates. Recently, we have developed a kinetic model of oligomer dynamics during amyloid aggregation. Here, we use this approach to derive explicit scaling relationships that reveal how key features of the time evolution of oligomers, including oligomer peak concentration and life-time, are controlled by the different rate parameters. We discuss the therapeutic implications of our framework by predicting changes in oligomer concentrations when the rates of the individual microscopic events are varied. Our results identify the kinetic parameters that control most effectively the generation of oligomers, thus opening the way for the systematic rational design of therapeutic strategies against amyloid-related diseases.

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