The major protein constituents of amyloid deposits in Alzheimer's disease (
AD) are the 40-residue beta -amyloid (A beta) (1-40) peptide and the 42-res
idue A beta (1-42) peptide. The A beta (1-42) is more pathogenic and produc
ed 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 A bet
a formation (beta -amyloidosis). During beta -amyloidosis, structural chang
es associated with the conversion of monomeric A beta peptide building bloc
ks 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 smo
ke, inhibits beta -amyloidosis of the A beta (1-42), which may result from
nicotine binding to the alpha -helical structure. These conclusions were ba
sed on solution nuclear magnetic resonance (NMR) spectroscopic studies with
the nonnative 28-residue A beta (1-28). This information suggests that, wh
en administered therapeutically to AD patients, nicotine may not only affec
t cholinergic activation, but could also conceivably alter amyloid depositi
on. In this report, NMR studies were augmented with the naturally occurring
A beta (1-42), under conditions where the peptide folds into a predominant
ly 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 bin
ding to a small, soluble beta -sheet aggregate that is NMR invisible. (C) 2
001 Society of Biological Psychiatry.