Nicotine and amyloid formation.
The major protein constituents of amyloid deposits in Alzheimer's disease (AD) are the 40-residue beta-amyloid (Abeta) (1-40) peptide and the 42-residue Abeta(1-42) peptide. The Abeta(1-42) is more pathogenic and produced in greater quantities in familial forms of AD. A major goal of research is to uncover a suitable inhibitor that either slows down or inhibits Abeta formation (beta-amyloidosis). During beta-amyloidosis, structural changes associated with the conversion of monomeric Abeta peptide building blocks into the aggregated fibrillar beta-sheet structures occur (alpha-helix-->beta-sheet or random, extended chain-->beta-sheet). In previous work, we and others established that nicotine, a major component of cigarette smoke, inhibits beta-amyloidosis of the Abeta(1-42), which may result from nicotine binding to the alpha-helical structure. These conclusions were based on solution nuclear magnetic resonance (NMR) spectroscopic studies with the nonnative 28-residue Abeta(1-28). This information suggests that, when administered therapeutically to AD patients, nicotine may not only affect cholinergic activation, but could also conceivably alter amyloid deposition. In this report, NMR studies were augmented with the naturally occurring Abeta(1-42), under conditions where the peptide folds into a predominantly alpha-helical or random, extended chain structure. The major result is that nicotine shows only modest binding to these conformations, indicating that the nicotine inhibition to beta-amyloidosis probably results from binding to a small, soluble beta-sheet aggregate that is NMR invisible.
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078, USA
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H
Zeng
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Zhang
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Peng
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Shao
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Menon
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Yang
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Salomon
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Freidland
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Zagorski
D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009538:Nicotine / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000378:metabolism; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D009538:Nicotine