title: Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide.
abstract: Disease related mutations and environmental factors are key determinants of the aggregation mechanism of the amyloid-β peptide implicated in Alzheimer's disease. Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the Aβ aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the individual underlying microscopic steps. We apply this work-flow to the disease-associated Aβ42-A2V variant, and to a variation in pH as examples of an intrinsic and an extrinsic perturbation. In both cases, our data reveal a shift towards a mechanism in which a larger fraction of the reactive flux goes via a pathway that generates potentially toxic oligomeric species in a fibril-catalyzed reaction. This is in agreement with the finding that Aβ42-A2V leads to early-onset Alzheimer's disease and enhances neurotoxicity.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB21EW, UK.
authors.forename: Georg
authors.initials: G
authors.lastname: Meisl
authors.affiliation: Department of Biochemistry and Structural Biology, Lund University, Lund, 22100, Sweden.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Structural Biology, Lund University, Lund, 22100, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Frohm
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge, CB21EW, UK.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Department of Biochemistry and Structural Biology, Lund University, Lund, 22100, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Linse
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009154:Mutation; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011994:Recombinant Proteins
chemical_list: D016229:Amyloid beta-Peptides; D066329:Protein Aggregates; D011994:Recombinant Proteins