title: Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides.
abstract: The two major forms of the amyloid-beta (Aβ) peptide found in plaques in patients suffering from Alzheimer's disease, Aβ40 and Aβ42, 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 Aβ40 peptide to identify the differences between Aβ40 and Aβ42 in terms of the microscopic determinants of the aggregation reaction. Our results reveal that the major source of aggregates in the case of Aβ40 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 Aβ42 compared with Aβ40, 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 Aβ and outlines a general approach toward achieving an understanding at the molecular level of the aberrant deposition of insoluble peptides in neurodegenerative disorders.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; and.
authors.forename: Georg
authors.initials: G
authors.lastname: Meisl
authors.affiliation: Chemistry Department and Molecular Protein Science, Lund University, SE221 00 Lund, Sweden.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Yang
authors.affiliation: Chemistry Department and Molecular Protein Science, Lund University, SE221 00 Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Hellstrand
authors.affiliation: Chemistry Department and Molecular Protein Science, Lund University, SE221 00 Lund, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Frohm
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; and.
authors.forename: Julius B
authors.initials: JB
authors.lastname: Kirkegaard
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; and.
authors.forename: Samuel I A
authors.initials: SI
authors.lastname: Cohen
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; and tpjk2@cam.ac.uk cmd44@cam.ac.uk Sara.Linse@biochemistry.lu.se.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Chemistry Department and Molecular Protein Science, Lund University, SE221 00 Lund, Sweden tpjk2@cam.ac.uk cmd44@cam.ac.uk Sara.Linse@biochemistry.lu.se.
authors.forename: Sara
authors.initials: S
authors.lastname: Linse
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; and tpjk2@cam.ac.uk cmd44@cam.ac.uk Sara.Linse@biochemistry.lu.se.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000503:physiopathology*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: aggregation mechanism; neurodegeneration; protein aggregation; rate law