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.
Highlights
(PAHs) with one to five aromatic rings, and the metal ions Cd(II), Cr(III), Pb(II), and Pb(IV)
All compounds were titrated to the Aβ solution in small steps, starting at sub-stoichiometric ratios, but only spectra for larger additions are shown where the interaction effects are most pronounced
Pb(IV) ions clearly induce loss of signal intensity in the NMR amide crosspeaks corresponding to certain N-terminal Aβ40 residues, indicating specific binding to this part of the peptide (Fig. 3A)
Summary
(PAHs) with one to five aromatic rings, and the metal ions Cd(II), Cr(III), Pb(II), and Pb(IV). While early studies were contradictory, there is general consensus that cigarette smoking increases AD risk when factors such as survival bias, competing risk, and tobacco industry affiliation of the researchers have been taken into account[26,27,28,29,30,31,32,33,34,35] Other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS)[36,37,38,39], multiple sclerosis (MS)[40] and Parkinson’s disease[41] appear to be more prevalent among smokers, the causes underlying these increased risks remain unclear. Debated are the possible neuroprotective effects of the parasympathomimetic stimulant nicotine, extracted from the tobacco plant (Nicotiana tabacum)[42,43,44,45,46]
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