Journal of Clinical Toxicology
Open Access

Abstract

Cotinine Inhibits Amyloid-ß Peptide Neurotoxicity and Oligomerization

Sarah Burgess, Ross Zeitlin and Valentina Echeverria

Alzheimer’s disease, the main cause of dementia, correlates with an increase in the brain levels of aggregated forms of amyloid-β (Aβ) peptide. We investigated the effect of cotinine, the main metabolite of nicotine, on Aβ 1-42 neurotoxicity. Compared to nicotine, cotinine has a longer plasma half-life, lower toxicity and is a poor agonist of the nicotinic acetylcholine receptors (nAChRs). We found that cotinine promoted the survival of primary cortical neurons exposed to Aβ 1-42 . This neuroprotective effect was independent of the agonistic activation of the nAChRs and it was not prevented by the general nAChR antagonist mecamylamine. However, it was prevented by the pre-aggregation of Aβ in absence of cotinine, suggesting that inhibition of Aβ 1-42 aggregation by cotinine is a key mechanism mediating its neuroprotective activity. The analysis of Aβ 1-42 aggregation using dot blot immunoassay showed that cotinine inhibits its oligomerization. These results suggest that cotinine is neuroprotective at least in part by preventing the aggregation of the amyloid peptide. We previously found that cotinine prevented memory loss and reduced plaques in the brain of Tg6799 mice. This study suggests that cotinine can also inhibit neuronal cell death induced by Aβ neurotoxicity.