title: Truncated Amyloid-β(11-40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly.
abstract: Alzheimer disease coincides with the formation of extracellular amyloid plaques composed of the amyloid-β (Aβ) peptide. Aβ is typically 40 residues long (Aβ(1-40)) but can have variable C and N termini. Naturally occurring N-terminally truncated Aβ(11-40/42) is found in the cerebrospinal fluid and has a similar abundance to Aβ(1-42), constituting one-fifth of the plaque load. Based on its specific N-terminal sequence we hypothesized that truncated Aβ(11-40/42) would have an elevated affinity for Cu(2+). Various spectroscopic techniques, complemented with transmission electron microscopy, were used to determine the properties of the Cu(2+)-Aβ(11-40/42) interaction and how Cu(2+) influences amyloid fiber formation. We show that Cu(2+)-Aβ(11-40) forms a tetragonal complex with a 34 ± 5 fm dissociation constant at pH 7.4. This affinity is 3 orders of magnitude tighter than Cu(2+) binding to Aβ(1-40/42) and more than an order of magnitude tighter than that of serum albumin, the extracellular Cu(2+) transport protein. Furthermore, Aβ(11-40/42) forms fibers twice as fast as Aβ(1-40) with a very different morphology, forming bundles of very short amyloid rods. Substoichiometric Cu(2+) drastically perturbs Aβ(11-40/42) assembly, stabilizing much longer fibers. The very tight fm affinity of Cu(2+) for Aβ(11-40/42) explains the high levels of Cu(2+) observed in Alzheimer disease plaques.
authors.affiliation: From the School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Barritt
authors.affiliation: From the School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom j.viles@qmul.ac.uk.
authors.forename: John H
authors.initials: JH
authors.lastname: Viles
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C000605560:amyloid beta-protein (11-40); C000605559:amyloid beta-protein (11-42); D003300:Copper
keywords: Alzheimer disease; affinity; albumin; amyloid; amyloid-β (AB); circular dichroism (CD); coordination; copper; fiber kinetics; metal ion-protein interaction