Simultaneous binding of heme and Cu with amyloid β peptides: active site and reactivities

Abstract

Amyloid imbalance and Aβ plaque formation are key histopathological features of Alzheimer’s disease (AD). These amyloid plaques observed in post-mortem AD brains have been found to contain increased levels of...

Studying Peptide-Metal Ion Complex Structures by Solution-State NMR

“…Binding to Ca(II) can be identified via chemical shift mapping of proton or heteroatom signals, as in the case of a six-amino acid peptide derived from the repetitive sequence in silk-moth silk. This peptide showed significant changes in 1D 13 C chemical shifts upon binding Ca(II), which was measured directly in solution. Whereas this only gave an indication of binding, it is a strong tool for identifying binding where necessary [103].…”

“…Metal-binding irregularities play a role in diseases such as Alzheimer's [13,14], ALS [15] and neurodegenerative disorders [6], among many others. Nickel and the essential metal, cobalt, are among the metals that can cause allergic reactions in humans [16].…”

“…Destabilization and misfolding caused by manganese-binding in prion disease [149] was studied with a 30-amino acid peptide comprising three repeats of a decapeptide repeat in the C-terminal region of the calcium protein, Cap43, that was probed using 1D 1 H-NMR to follow line-broadening upon binding and elucidate the role of divalent ions in the pathogenesis of prion disease [150]. Mn(II) ion binding to a peptide derived from amyloid beta, Aβ (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), was also studied by measuring line-broadening upon binding by 1D 1 H-NMR [151].…”

“…A model of the structure of a complex of Co(II) and a fragment of amyloid beta protein, Aβ (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), was determined by canonical methodology on a sample with a 1:0.01 molar ratio of peptide-to-cobalt. The intensity of the signals were measured as a function of titration and signals with reduced intensity were considered to be proximate to the cobalt ion and served as the cobalt binding center [151].…”

Spin state dependent peroxidase activity of heme bound amyloid β peptides relevant to Alzheimer's disease

“…[25][26][27] The perturbation of heme (and hence iron) metabolism is observed in the AD brain, which manifests itself as heme deciency symptoms such as lower levels of heme a (26%), a possible compensatory increase in heme b (250%), mitochondrial complex IV dysfunction, unregulated iron accumulation, over expression of heme oxygenase, biliverdin reductase A, ferrochelatase, elevated levels of heme degradation products like bilirubin etc. 4,22,[27][28][29][30][31] Apart from the brain, changes in the iron and heme homeostasis are also observed in the blood of AD patients in the form of lowering of haemoglobin and peripheral iron levels as well as identication of anaemia, which is common in elderly individuals, as a risk factor for the disease. [32][33][34] All these ndings are suggestive of a link between the heme regulatory pathway and AD.…”