Can smoking have a neuroprotective effect? The recent observation that exposure to nicotine delays the onset of Alzheimer's disease has researchers racing to identify the mechanism of this surprising phenomenon. Most studies have focused on nicotine itself — few have considered the contribution that metabolites of nicotine, the principal alkaloid component of tobacco, might make to neuroprotection. Now, a study published in the Proceedings of the National Academy of Sciences shows that nornicotine — a product of the N-demethylation of nicotine — inhibits the formation of the amyloid β-peptide (Aβ) fibrils whose aggregation into neuritic plaques is a hallmark of this devastating disease.

As glycation reactions between amines and reducing sugars have recently been implicated in Alzheimer's disease, and nornicotine is known to catalyse aberrant glycation of proteins in vivo, Tobin Dickerson and Kim Janda explored the hypothesis that nornicotine might be active against Aβ. Following incubation of a 40-amino-acid fragment of Aβ with nornicotine and glucose, mass spectrometry indicated that one glucose and one nornicotine molecule were being added to some of the peptide fragments, resulting in an 18% reduction in fibril formation.

Nuclear magnetic resonance spectroscopic investigations indicated that covalent bonds form between the pyrrolidine ring of nornicotine and a lysine residue of the peptide that the authors suggest is essential to the aggregation of Aβ. This assertion is supported by the finding that nornicotine had no effect on preformed fibrils, in which the target lysine residue is 'buried' within a hydrophobic core and is therefore not available for covalent modification.

These new data show that searching for compounds that covalently interact with Aβ might facilitate the development of much-needed treatments for Alzheimer's disease, which is predicted to afflict 22 million people worldwide within the next 20 years. Unfortunately, the considerable toxicity and psychoactivity of nicotine and nornicotine severely limits their therapeutic potential. Sorry to disappoint the smokers among you, but it's unlikely that physicians will be prescribing cigarettes any time soon.