Anti-fibrillogenic and fibril-destabilizing activity of nicotine in vitro: Implications for the prevention and therapeutics of Lewy body diseases

The aggregation of alpha-synuclein (αS) has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Both retrospective and prospective epidemiological studies have consistently demonstrated an inverse association between cigarette smoking and Parkinson's disease (PD). We used fluorescence spectroscopy with thioflavin S, electron microscopy and atomic force microscopy to examine the effects of nicotine, pyridine, and N-methylpyrrolidine on the formation of αS fibrils (fαS) from wild-type αS (αS (WT)) and A53T mutant αS (A53T) and on preformed fαSs. Nicotine dose-dependently inhibited the fαS formation from both αS (WT) and A53T. Moreover, nicotine dose-dependently destabilized preformed fαSs. These effects of nicotine were similar to those of N-methylpyrrolidine. The anti-fibrillogenic activity of nicotine may be exerted not only by the inhibition of fαS formation but also by the destabilization of preformed fαS. Additionally, this effect may be attributed to N-methylpyrrolidine moieties of nicotine.