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

ABSTRACT: The two major forms of the amyloid-beta (A?) peptide found in plaques in patients suffering from Alzheimer's disease, A?40 and A?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?40 peptide to identify the differences between A?40 and A?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?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?42 compared with A?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? and outlines a general approach toward achieving an understanding at the molecular level of the aberrant deposition of insoluble peptides in neurodegenerative disorders.

SUBMITTER: Meisl G 

PROVIDER: S-EPMC4084462 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature