The 42-residue -(1-42) peptide is the major protein component of amyloid plaque cores in Alzheimer's disease. In aqueous solution at physiological pH, the synthetic -(1-42) peptide readily aggregates and precipitates as oligomeric -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 -(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 Nmethylpyrrolidine accelerate the aggregation process. Nuclear magnetic resonance (NMR) studies demonstrate that nicotine binds to the 1-28 peptide region when folded in an R-helical conformation. On the basis of chemical shift data, the binding primarily involves the N-CH 3 and 5′CH 2 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 R-helix f -sheet conformational transformation that is important in the pathogenesis of Alzheimer's disease.

The three-dimensional solution structure of residues 1-28 of the amyloid beta-peptide was determined using nuclear magnetic resonance spectroscopy, distance geometry, and molecular dynamic techniques. The nuclear magnetic resonance data used to derive the structure consisted of nuclear Overhauser enhancements, vicinal coupling constants, and temperature coefficients of the amide-NH chemical shifts. The beta-peptide is the major proteinaceous component of amyloid deposits in Alzheimer's disease. In membrane-like media, the peptide folds to form a predominately alpha-helical structure with a bend centered at residue 12. The side chains of histidine-13 and lysine-16 are close, residing on the same face of the helix. Their proximity may constitute a binding motif with the heparan sulfate proteoglycans. The molecular details of the structure shown here could facilitate the design of rational treatments to curtail the binding of heparan sulfate proteoglycans or to prevent an alpha-helix-->beta-sheet conversion that may occur during the early stages of amyloid formation in Alzheimer's disease.

The major protein constituent of amyloid deposits in Alzheimer's disease is the β-peptide, which in solution can fold as a random coil, monomeric α-helix, or oligomeric β-sheet structure, the latter structure being toxic and eventually precipitating as amyloid. In this report, using circular dichroism and nuclear magnetic resonance spectroscopic techniques, we demonstrate that in micelle solution the α-helical structure is the predominate structural motif and that its stability is highly dependent on the pH and the surface charge of the micelle. A peptide fragment comprised of residues 1−28 of the β-peptide [β-(1−28)], which occupies the presumed extracellular domain of the amyloid precursor protein and the negatively charged sodium dodecyl sulfate (SDS), the positively charged dodecyltrimethylammonium chloride (DTAC), and the zwitterionic, neutral dodecylphosphocholine (DPC), was utilized. In SDS and DPC, nuclear Overhauser enhancement spectroscopy and the αH chemical shifts showed that at pH 2−3 there are two α-helical regions located within the Ala2−Asp7 and Tyr10−Lys28 peptide regions. Temperature coefficients for the amide-NH established that the 1−28 region is located at the micelle surface and does not insert into the hydrophobic interior. Above pH 4, no α-helix forms in DPC, whereas the Tyr10−Lys28 helix remained α-helical in SDS up to pH 9.5. With DTAC, the α-helix formed at high pH, and below pH 4 only random coil was present. Most importantly, the present data demonstrate that micelles prevent formation of the toxic β-sheet structure for the 1−28 region, which may eventually have therapeutic implications for the treatment of Alzheimer's disease.

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