Truncated Amyloid-{beta}(11-40/42) from Alzheimer’s Disease Binds Copper2+ with a Femtomolar Affinity and Influences Fibre Assembly [Molecular Biophysics]

September 25th, 2015 by Barritt, J. D., Viles, J. H.

Alzheimer's disease (AD) coincides with the formation of extracellular amyloid plaques composed of the amyloid-β (Aβ) peptide. Aβ is typically forty 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 Cu2+. Various spectroscopic techniques, complimented with transmission electron microscopy, were used to determine the properties of the Cu2+Aβ(11-40/42) interaction and how Cu2+ influences amyloid fibre formation. We show, Cu2+Aβ(11-40) forms a tetragonal complex with a 34 ± 5 femtomolar dissociation constant at pH 7.4. This affinity is three orders of magnitude tighter than Cu2+ binding to Aβ(1-40/42) and more than an order of magnitude tighter than that of serum albumin, the extracellular Cu2+ transport protein. Furthermore, Aβ(11-40/42) forms fibres twice as fast as Aβ(1-40) with a very different morphology; forming bundles of very short amyloid rods. Substoichiometric Cu2+ drastically perturbs Aβ(11-40/42) assembly, stabilizing much longer fibres. The very tight femtomolar affinity of Cu2+ for Aβ(11-40/42) explains the high levels of Cu2+ observed in AD plaques.
  • Posted in Journal of Biological Chemistry, Publications
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