Abstract
Brains and blood of Alzheimer’s disease (AD) patients have shown elevated mercury concentrations, but potential involvement of mercury exposure in AD pathogenesis has not been studied at the molecular level. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. Aβ peptide fibrillization is known to be modulated by metal ions such as Cu(II) and Zn(II). Here, we study in vitro the interactions between Aβ peptides and Hg(II) ions by multiple biophysical techniques. Fluorescence spectroscopy and atomic force microscopy (AFM) show that Hg(II) ions have a concentration-dependent inhibiting effect on Aβ fibrillization: at a 1:1 Aβ·Hg(II) ratio only non-fibrillar Aβ aggregates are formed. NMR spectroscopy shows that Hg(II) ions interact with the N-terminal region of Aβ(1–40) with a micromolar affinity, likely via a binding mode similar to that for Cu(II) and Zn(II) ions, i.e., mainly via the histidine residues His6, His13, and His14. Thus, together with Cu(II), Fe(II), Mn(II), Pb(IV), and Zn(II) ions, Hg(II) belongs to a family of metal ions that display residue-specific binding interactions with Aβ peptides and modulate their aggregation processes.
Highlights
Alzheimer’s disease (AD) is a progressive, irreversible, and currently incurable neurodegenerative disorder, and the leading cause of dementia worldwide [1,2]
The major characteristic AD lesion in the brain is the presence of extracellular amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into insoluble fibrils [30] that display the cross-β secondary structure common for many amyloid fibrils [31,32]
The Aβ fibrils and plaques are the end-product of an Aβ aggregation process [37,39,40] involving extra- and/or intracellular formation of intermediate, soluble, and likely neurotoxic Aβ oligomers [41,42,43,44] that may transfer from neuron to neuron via exosomes [45,46]
Summary
Alzheimer’s disease (AD) is a progressive, irreversible, and currently incurable neurodegenerative disorder, and the leading cause of dementia worldwide [1,2]. Aβ42 oligomers appear to be the most cell-toxic [43], and oligomer formation appears to be influenced by both hydrophobic and electrostatic effects originating from interactions with, e.g., cellular membranes, metal ions, small molecules, and other proteins [24,37,47,48,49,50,51,52,53,54,55,56]
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