title: Expression in drosophila of tandem amyloid β peptides provides insights into links between aggregation and neurotoxicity.
abstract: The generation and subsequent aggregation of amyloid β (Aβ) peptides play a crucial initiating role in the pathogenesis of Alzheimer disease (AD). The two main isoforms of these peptides have 40 (Aβ(40)) or 42 residues (Aβ(42)), the latter having a higher propensity to aggregate in vitro and being the main component of the plaques observed in vivo in AD patients. We have designed a series of tandem dimeric constructs of these Aβ peptides to probe the manner in which changes in the aggregation kinetics of Aβ affect its deposition and toxicity in a Drosophila melanogaster model system. The levels of insoluble aggregates were found to be substantially elevated in flies expressing the tandem constructs of both Aβ(40) and Aβ(42) compared with the equivalent monomeric peptides, consistent with the higher effective concentration, and hence increased aggregation rate, of the peptides in the tandem repeat. A unique feature of the Aβ(42) constructs, however, is the appearance of high levels of soluble oligomeric aggregates and a corresponding dramatic increase in their in vivo toxicity. The toxic nature of the Aβ(42) peptide in vivo can therefore be attributed to the higher kinetic stability of the oligomeric intermediate states that it populates relative to those of Aβ(40) rather than simply to its higher rate of aggregation.
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Speretta
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Jahn
authors.forename: Gian Gaetano
authors.initials: GG
authors.lastname: Tartaglia
authors.forename: Giorgio
authors.initials: G
authors.lastname: Favrin
authors.forename: Teresa P
authors.initials: TP
authors.lastname: Barros
authors.forename: Sara
authors.initials: S
authors.lastname: Imarisio
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Leila M
authors.initials: LM
authors.lastname: Luheshi
authors.forename: Damian C
authors.initials: DC
authors.lastname: Crowther
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D015870:Gene Expression; D006801:Humans; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)