NICOTINE INHIBITS AMYLOID FORMATION BY THE BETA-PEPTIDE

The 42-residue beta-(1-42) peptide is the major protein component of a myloid plaque cores in Alzheimer's disease. In aqueous solution at phy siological pH, the synthetic beta-(1-42) peptide readily aggregates an d precipitates as oligomeric beta-sheet structures, a process that occ urs during amyloid formation in Alzheimer's disease. Using circular di chroism (CD) and ultraviolet spectroscopic techniques, we show that ni cotine, a major component in cigarette smoke, inhibits amyloid formati on by the beta-(1-42) peptide. The related compound cotinine, the majo r 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 bin ds to the 1-28 peptide region when folded in an alpha-helical conforma tion. On the basis of chemical shift data, the binding primarily invol ves the N-CH3 and 5'CH2 pyrrolidine moieties of nicotine and the histi dine residues of the peptide. The binding is in fast exchange, as show n by single averaged NMR peaks and the lack of-nuclear Overhauser enha ncement data between nicotine and the peptide in two-dimensional NOESY spectra. A mechanism is preposed, whereby nicotine retards amyloidosi s by preventing an alpha-helix-->beta-sheet conformational transformat ion that is important in the pathogenesis of Alzheimer's disease.