Characterization of Mn(II) ion binding to the amyloid-β peptide in Alzheimer⿿s disease

Abstract

Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer⿿s disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-β (Aβ) peptides. Previous studies have shown that Aβ displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate Aβ aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the Aβ(1⿿40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to Aβ may not have a large effect on the peptide⿿s aggregation into amyloid fibrils. However, identification of an additional metal ion displaying Aβ binding reveals more complex AD metal chemistry than has been previously considered in the literature.