Concentration-dependent effects of mercury and lead on A42: possible implications for Alzheimer's disease

Mercury (Hg) and lead (Pb) are known to be toxic non-radioactive elements, with well-described neurotoxicology. Much evidence supports the implication of metals as potential risk cofactors in Alzheimer's disease (AD). Although the action mechanism of the two metals remains unclear, Hg and Pb toxicity in AD could depend on their ability to favour misfolding and aggregation of amyloid beta proteins (As) that seem to have toxic properties, particularly in their aggregated state. In our study, we evaluated the effect of Hg and Pb both on the A42 ion channel incorporated in a planar lipid membrane made up of phosphatidylcholine containing 30% cholesterol and on the secondary structure of A42 in an aqueous environment. The effects of Hg and Pb on the A42 peptide were observed for its channel incorporated into a membrane as well as for the peptide in solution. A decreasing A42 channel frequency and the formation of large and amorphous aggregates in solution that are prone to precipitate were both dependent on metal concentration. These experimental data suggest that Hg and Pb interact directly with As, strengthening the hypothesis that the two metals may be a risk factor in AD.