Nicotine inhibits amyloid formation by the beta-peptide

Biochemistry. 1996 Oct 22;35(42):13568-78. doi: 10.1021/bi9617264.


The 42-residues beta-(1-42) peptide is the major protein component of amyloid plaque cores in Alzheimer's disease. In aqueous solution at physiological pH, the synthetic beta-(1-42) peptide readily aggregates and precipitates as oligomeric beta-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 beta-(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 alpha-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 alpha-helix-->beta-sheet conformational transformation that is important in the pathogenesis of Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism*
  • Amyloidosis / metabolism
  • Chemical Precipitation
  • Circular Dichroism
  • Cotinine / pharmacology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Sequence Data
  • Molecular Structure
  • Nicotine / metabolism
  • Nicotine / pharmacology*
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism*
  • Protein Binding
  • Protein Structure, Secondary / drug effects*
  • Pyridines / pharmacology
  • Pyrrolidines / pharmacology
  • Spectrophotometry, Ultraviolet


  • Amyloid beta-Peptides
  • Peptide Fragments
  • Pyridines
  • Pyrrolidines
  • amyloid beta-protein (1-42)
  • N-methylpyrrolidine
  • Nicotine
  • Cotinine
  • pyridine