Nicotine Inhibits Amyloid Formation by the β-Peptide

Abstract

The 42-residue β-(1−42) peptide is the major protein component of amyloid plaque cores in Alzheimer's disease. In aqueous solution at physiological pH, the synthetic β-(1−42) peptide readily aggregates and precipitates as oligomeric β-sheet structures, a process that occurs during amyloid formation in Alzheimer's disease. Using circular dichroism (CD) and ultraviolet spectroscopic techniques, we show that nicotine, a major component in cigarette smoke, inhibits amyloid formation by the β-(1−42) peptide. The related compound cotinine, the major metabolite of nicotine in humans, also slows down amyloid formation, but to a lesser extent than nicotine. In contrast, control substances pyridine and N-methylpyrrolidine accelerate the aggregation process. Nuclear magnetic resonance (NMR) studies demonstrate that nicotine binds to the 1−28 peptide region when folded in an α-helical conformation. On the basis of chemical shift data, the binding primarily involves the N-CH₃ and 5‘CH₂ pyrrolidine moieties of nicotine and the histidine residues of the peptide. The binding is in fast exchange, as shown by single averaged NMR peaks and the lack of nuclear Overhauser enhancement data between nicotine and the peptide in two-dimensional NOESY spectra. A mechanism is proposed, whereby nicotine retards amyloidosis by preventing an α-helix → β-sheet conformational transformation that is important in the pathogenesis of Alzheimer's disease.