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

Abstract

Background: N-terminally truncated A␤ (11-40/42) typically constitutes 19% of plaque load in Alzheimer patients. Results: Cu 2ϩ binds to A␤ with a 34-fM dissociation constant and stabilizes very short highly amyloidogenic amyloid rods into longer A␤ fibers. Concussion: The very tight affinity explains the high levels of Cu 2ϩ in amyloid plaques. Significance: Copper, tightly bound to A␤ (11-40/42) , may influence disease pathology.

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…[103,104] Such affinity is perfectly in line with those of other ATCUN peptides. [109,110] Note that a secondary Cu II site is present in A [4][5][6][7][8][9][10][11][12][13][14][15][16] and is relatively weak (K a = 10 6.7 M -1 at pH = 7.4) and separated from the N-terminal site.…”

“…More generally, N-terminally truncated peptides might also be considered for new therapeutic targets. [9] To conclude, and as previously pointed out in seminal works, [103,104,111,134,136] the interaction of Cu II with N-terminally truncated peptides might reshape our current view of the deleterious impact of Cu II binding to amyloid-peptides.…”

“…[77,97,98] The ATCUN coordination mode of Cu II to A 4-n and to A 11-n is predominant from pH 5, whereas deprotonation of outer-sphere and non-binding side chains occurs when the pH is increased. [103][104][105] A weak fifth ligand, a water molecule, can be present as an apical ligand. This coordination is analogous to the one proposed for the DAHK tetrapeptide, the N-terminal sequence of human serum albumin, the structure of which was resolved by means of X-ray diffraction.…”

“…[112] A forms fibrils faster than A 1-40 and A , and it does co-assemble with A 1-40 but not with A . [104,113] Addition of Cu II to A 11-28/40/42 seems to preclude fibrillary aggregation, [104,114,115] likely as a result of the strong 1:1 Cu II -ATCUN coordination that destabilizes the peptide-peptide interactions required for the nucleation of the aggregation process. [44] …”

Multifactorial Analysis of a Biomarker Pool for Alzheimer Disease Risk in a North Indian Population

“…However, no difference was reported in another study by van Wymelbeke et al [52] involving hospitalized PwAD in France. Albumin is known to be involved in the extracellular transport of the Cu 2+ and it also interacts with Aβ peptides [53,54,55]. Further, its role as molecular chaperone has also been proposed [56], and reduction in albumin concentration from human plasma was found to significantly increase aggregation under physiological stresses [56].…”