The Elevated Copper Binding Strength of Amyloid-β Aggregates Allows the Sequestration of Copper from Albumin: A Pathway to Accumulation of Copper in Senile Plaques

Copper coexists with amyloid-beta (A beta) peptides at a high concentration in the senile plaques of Alzheimer's disease (AD) patients and has been linked to oxidative damage associated with AD pathology. However, the origin of copper and the driving force behind its accumulation are unknown. We designed a sensitive fluorescent probe, A beta(1-16)(Y10W), by substituting the tyrosine residue at position 10 in the hydrophilic domain of A beta(1-42) with tryptophan. Upon mixing Cu(II), A beta(1-16)(Y10W), and aliquots of A beta(1-42) taken from samples incubated for different lengths of time, we found that the Cu(II) binding strength of aggregated A beta(1-42) has been elevated by more than 2 orders of magnitude with respect to that of monomeric A beta(1-42). Electron paramagnetic spectroscopic measurements revealed that the A beta(1-42) aggregates, unlike their monomeric form, can seize copper from human serum albumin, an abundant copper-containing protein in brain and cerebrospinal fluid. The significantly elevated binding strength of the A beta(1-42) aggregates can be rationalized by a Cu(II) coordination sphere constituted by three histidines from two adjacent A beta(1-42) molecules. Our work demonstrates that the copper binding affinity of A beta(1-42) is dependent on its aggregation state and provides new insight into how and why senile plaques accumulate copper in vivo.