Differences in nucleation behavior underlie the contrasting aggregation kinetics of the A beta 40 and A beta 42 peptides

作者：Meisl, Georg; Yang, Xiaoting; Hellstrand, Erik; Frohm, Birgitta; Kirkegaard, Julius B.; Cohen, Samuel I. A.; Dobson, Christopher M.^*; Linse, Sara; Knowles, Tuomas P. J.

来源：Proceedings of the National Academy of Sciences, 2014, 111(26): 9384-9389.

DOI：10.1073/pnas.1401564111

• protein aggregation
• rate law
• neurodegeneration
• aggregation mechanism

The two major forms of the amyloid-beta (A beta) peptide found in plaques in patients suffering from Alzheimer's disease, A beta 40 and A beta 42, only differ by two amino acids in the C-terminal region, yet they display markedly different aggregation behavior. The origins of these differences have remained challenging to connect to specific molecular-level processes underlying the aggregation reaction. In this paper we use a general strategy to apply the conventional workflow of chemical kinetics to the aggregation of the A beta 40 peptide to identify the differences between A beta 40 and A beta 42 in terms of the microscopic determinants of the aggregation reaction. Our results reveal that the major source of aggregates in the case of A beta 40 is a fibril-catalyzed nucleation process, the multistep nature of which is evident through its saturation behavior. Moreover, our results show that the significant differences in the observed behavior of the two proteins originate not simply from a uniform increase in all microscopic rates for A beta 42 compared with A beta 40, but rather are due to a shift of more than one order of magnitude in the relative importance of primary nucleation versus fibril-catalyzed secondary nucleation processes. This analysis sheds light on the microscopic determinants of the aggregation behavior of the principal forms of A beta and outlines a general approach toward achieving an understanding at the molecular level of the aberrant deposition of insoluble peptides in neurodegenerative disorders.

• 出版日期2014-7-1