Alzheimer’s disease and cigarette smoke components: effects of nicotine, PAHs, and Cd(II), Cr(III), Pb(II), Pb(IV) ions on amyloid-β peptide aggregation

Abstract

Cigarette smoking is a significant risk factor for Alzheimer’s disease (AD), which is associated with extracellular brain deposits of amyloid plaques containing aggregated amyloid-β (Aβ) peptides. Aβ aggregation occurs via multiple pathways that can be influenced by various compounds. Here, we used AFM imaging and NMR, fluorescence, and mass spectrometry to monitor in vitro how Aβ aggregation is affected by the cigarette-related compounds nicotine, polycyclic aromatic hydrocarbons (PAHs) with one to five aromatic rings, and the metal ions Cd(II), Cr(III), Pb(II), and Pb(IV). All PAHs and metal ions modulated the Aβ aggregation process. Cd(II), Cr(III), and Pb(II) ions displayed general electrostatic interactions with Aβ, whereas Pb(IV) ions showed specific transient binding coordination to the N-terminal Aβ segment. Thus, Pb(IV) ions are especially prone to interact with Aβ and affect its aggregation. While Pb(IV) ions affected mainly Aβ dimer and trimer formation, hydrophobic toluene mainly affected formation of larger aggregates such as tetramers. The uncharged and hydrophilic nicotine molecule showed no direct interactions with Aβ, nor did it affect Aβ aggregation. Our Aβ interaction results suggest a molecular rationale for the higher AD prevalence among smokers, and indicate that certain forms of lead in particular may constitute an environmental risk factor for AD.

Metal binding to the amyloid-β peptides in the presence of biomembranes: potential mechanisms of cell toxicity

“…At lower pH, alternative binding ligands have been observed [20]. Metal ions such as Fe(II) [22], Mn(II) [23], and Pb(IV) [24] also display binding sites that mainly involve the Aβ histidines, possibly in combination with the negatively charged Asp and Glu residues [23] or the Tyr10 residue [24]. Different interactions have been observed for different ions of the same metal, e.g., Cu(I)/Cu(II) and Pb(II)/Pb(IV) ions [24,25].…”

“…Metal ions such as Fe(II) [22], Mn(II) [23], and Pb(IV) [24] also display binding sites that mainly involve the Aβ histidines, possibly in combination with the negatively charged Asp and Glu residues [23] or the Tyr10 residue [24]. Different interactions have been observed for different ions of the same metal, e.g., Cu(I)/Cu(II) and Pb(II)/Pb(IV) ions [24,25]. As many different metal ions can bind the Aβ N-terminal part with similar coordination ligands and binding affinities, binding competition between different metal ions with different properties-such as redox-active and non-redox-active ions-might be of biological relevance in AD pathology.…”

“…One in vivo study showed that addition of Zn(II) or removal of Ca(II) ions inhibited Aβ toxicity, while addition of Cd(II) ions (which are known inhibitors of native calcium channels) or antioxidants did not [66,67]. This might be related to Zn(II) but not Cd(II) ions displaying specific binding to the Aβ N-terminal region [18,24], as another study showed that various ions and molecules that interact specifically with the Aβ His13 and His14 residues could block leakage in planar lipid bilayers, and stop cytotoxicity in rat neurons [68], thus indicating similar mechanisms in artificial and biological membranes. Zinc ions have interestingly also been shown to block the leakage caused by truncated Aβ peptides that lack the metal-binding domain, such as Aβ [69].…”

Nanoscale Discrimination between Toxic and Nontoxic Protein Misfolded Oligomers with Tip‐Enhanced Raman Spectroscopy

“…Thus, the intense TERS signals emerging from our investigation in the case of His and the aromatic amino acids in type A species (Figure ) provide a direct confirmation of a peculiar superficial structuring existing on toxic misfolded species that causes cellular dysfunction. Interestingly, the presence of top signals as observed for amino acid residues of toxic species containing reactive side chains such as imidazole in His and phenol in Tyr (Figure ), is suggestive of the importance of such exposed moieties in neuronal membrane interactions …”

A Preliminary Study of Cu Exposure Effects upon Alzheimer’s Amyloid Pathology

“…Copper also fuels inflammatory factors in the brain [31], and has been implicated in mitochondrial dysfunction, which is a characteristic of AD, and processes involving the beta-secretase protein (BACE1) [32,33]. It should be noted that other non-essential metals have also been associated with AD, such as mercury [34] and lead [35][36][37], among others [36,37].…”