Binding of Hg(I) and Hg(II) Ions to Amyloid-Beta (Aβ) Peptide Variants Affect their Structure and Aggregation.

Mercury (Hg) exposure is a possible risk factor for Alzheimer's disease (AD). Some studies reported higher Hg levels in AD patients, but evidence is inconclusive. Mechanisms linking Hg exposure to AD neuropathology remain to be found. The hallmark of AD brains is deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides. Here, we use transmission electron microscopy and biophysical spectroscopy techniques to study in vitro interactions between inorganic Hg and pathologically relevant Aβ(1-40) and Aβ(4-40) variants and the Aβ(1-40)(H6A, H13A, H14A) mutant. For the first time, effects on Aβ aggregation of both Hg(I) and Hg(II) are compared. Hg(II) binds Aβ(1-40) with apparent binding affinity of 28 ± 8 μM, at 20 °C in 20 mM MES buffer, pH 7.3. The N-terminal His6, His13, and His14 residues are involved in binding coordination. Hg(II) binding induces structural alterations (coil-coil interactions) in Aβ monomers positioned in membrane-mimicking SDS micelles. Equimolar amounts of either Hg(I) or Hg(II) inhibit normal Aβ fibrillation by directing aggregation towards forming large amorphous aggregates. All these structural rearrangements may be relevant for the harmful Aβ aggregation processes involved in AD brain pathology. Inducing protein misfolding and aggregation might be a general toxic mechanism of mercury.