Truncated Amyloid-β(11-40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

Alzheimer disease coincides with the formation of extracellular amyloid plaques composed of the amyloid-beta (A beta) peptide. A beta is typically 40 residues long (A beta((1-40))) but can have variable C and N termini. Naturally occurring N-terminally truncated A beta((11-40/42)) is found in the cerebrospinal fluid and has a similar abundance to A beta((1-42)), constituting one-fifth of the plaque load. Based on its specific N-terminal sequence we hypothesized that truncated A beta((11-40/42)) would have an elevated affinity for Cu2+. Various spectroscopic techniques, complemented with transmission electron microscopy, were used to determine the properties of the Cu2+ -A beta((11-40/42)) interaction and how Cu2+ influences amyloid fiber formation. We show that Cu2+ -A beta((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 Cu2+ binding to A beta((1-40/42)) and more than an order of magnitude tighter than that of serum albumin, the extracellular Cu2+ transport protein. Furthermore, A beta((11-40/42)) forms fibers twice as fast as A beta((1-40)) with a very different morphology, forming bundles of very short amyloid rods. Substoichiometric Cu2+ drastically perturbs A beta((11-40/42)) assembly, stabilizing much longer fibers. The very tight fM affinity of Cu2+ for A beta((11-40/42)) explains the high levels of Cu2+ observed in Alzheimer disease plaques.