title: Structural basis for increased toxicity of pathological aβ42:aβ40 ratios in Alzheimer disease.
abstract: The β-amyloid peptide (Aβ) is directly related to neurotoxicity in Alzheimer disease (AD). The two most abundant alloforms of the peptide co-exist under normal physiological conditions in the brain in an Aβ(42):Aβ(40) ratio of ∼1:9. This ratio is often shifted to a higher percentage of Aβ(42) in brains of patients with familial AD and this has recently been shown to lead to increased synaptotoxicity. The molecular basis for this phenomenon is unclear. Although the aggregation characteristics of Aβ(40) and Aβ(42) individually are well established, little is known about the properties of mixtures. We have explored the biophysical and structural properties of physiologically relevant Aβ(42):Aβ(40) ratios by several techniques. We show that Aβ(40) and Aβ(42) directly interact as well as modify the behavior of the other. The structures of monomeric and fibrillar assemblies formed from Aβ(40) and Aβ(42) mixtures do not differ from those formed from either of these peptides alone. Instead, the co-assembly of Aβ(40) and Aβ(42) influences the aggregation kinetics by altering the pattern of oligomer formation as evidenced by a unique combination of solution nuclear magnetic resonance spectroscopy, high molecular weight mass spectrometry, and cross-seeding experiments. We relate these observations to the observed enhanced toxicity of relevant ratios of Aβ(42):Aβ(40) in synaptotoxicity assays and in AD patients.
authors.affiliation: Division of Molecular Structure, Medical Research Council National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
authors.forename: Kris
authors.initials: K
authors.lastname: Pauwels
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Williams
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Morris
authors.forename: Wim
authors.initials: W
authors.lastname: Jonckheere
authors.forename: Annelies
authors.initials: A
authors.lastname: Vandersteen
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
authors.forename: Louise C
authors.initials: LC
authors.lastname: Serpell
authors.forename: Kerensa
authors.initials: K
authors.lastname: Broersen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)