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Elevated Copper Binding Strength of Amyloid-β Aggregates Enables Their Copper Sequestration from Albumin: a Pathway to Accumulation of Copper in Senile Plaques.

Biochemistry. 2012 Dec 13;

Authors: Jiang D, Zhang L, Grant GP, Dudzik CG, Chen S, Patel S, Hao Y, Millhauser GL, Zhou F


Copper coexists with amyloid-β (Aβ) 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, Aβ(1-16)(Y10W), by substituting the tyrosine residue at position 10 in the hydrophilic domain of Aβ(1-42) with tryptophan. Upon mixing Cu(II), Aβ(1-16)(Y10W), and aliquots of Aβ(1-42) taken from samples incubated for different lengths of time, we found that the Cu(II) binding strength of aggregated Aβ(1-42) has been elevated by more than two orders of magnitude with respect to that of monomeric Aβ(1-42). Electron paramagnetic spectroscopic measurements revealed that the Aβ(1-42) aggregates, unlike their monomeric form, can seize copper from human serum albumin (HSA), an abundant copper-containing protein in brain and cerebrospinal fluid. The significantly elevated binding strength of the Aβ(1-42) aggregates can be rationalized by a Cu(II) coordination sphere constituted by three histidines from two adjacent Aβ(1-42) molecules. Our work demonstrates that the copper binding affinity by Aβ(1-42) is dependent on its aggregation state and provides new insight into how and why senile plaques accumulate copper in vivo.

PMID: 23237523 [PubMed - as supplied by publisher]