title: 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.
abstract: 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 2 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, 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 of Aβ(1-42) is dependent on its aggregation state and provides new insight into how and why senile plaques accumulate copper in vivo.
authors.affiliation: Department of Chemistry and Biochemistry, California State University, Los Angeles, Los Angeles, CA 90032, USA.
authors.forename: Dianlu
authors.initials: D
authors.lastname: Jiang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Gian Paola G
authors.initials: GP
authors.lastname: Grant
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Dudzik
authors.forename: Shu
authors.initials: S
authors.lastname: Chen
authors.forename: Sveti
authors.initials: S
authors.lastname: Patel
authors.forename: Yuanqiang
authors.initials: Y
authors.lastname: Hao
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
mesh_terms: D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002850:Chromatography, Gel; D003300:Copper / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D008970:Molecular Weight; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism*; D011489:Protein Denaturation; D012709:Serum Albumin / Q000378:metabolism*; D000075462:Serum Albumin, Human; D013050:Spectrometry, Fluorescence; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism
chemical_list: C422455:ALB protein, human; D016229:Amyloid beta-Peptides; D050505:Mutant Proteins; D010446:Peptide Fragments; D012709:Serum Albumin; C433241:amyloid beta-protein (1-16); C075222:amyloid beta-protein (1-42); D006639:Histidine; D003300:Copper; D014364:Tryptophan; D000075462:Serum Albumin, Human