P3‐290: Cotinine: A dual‐action drug with multiple benefits against Alzheimer's disease

Epidemiological studies show that smoking negatively correlates with the incidence of Alzheimer's disease (AD). We investigated the effects of cotinine, the main metabolite of nicotine, against AD and its effect on plaque deposition and memory in the very rapid AD amyloid model (5xFAD Tg 6799 mice). Additionally, we examined the effect of cotinine on amyloid beta (Abeta) aggregation and the activity of the alpha7- and alpha4/beta2-nicotinic acetylcholine receptors (nAChRs). The effect of cotinine on Abeta aggregation in vitro was studied by using Western blot, dot-blot immunoassays, atomic force microscopy, and x-ray diffraction. To investigate the effect of cotinine in vivo, we treated transgenic Tg6799 and control mice with cotinine (2.5mg/kg) and tested them using radial arm water maze, circular platform, and interference tests. The analysis of Abeta levels and deposition was performed using immunohistochemical and ELISA techniques. The effect of cotinine over nAChR activity was evaluated using voltage clamp and heterologously expressed nAChRs in Xenopus laevis oocytes. Molecular dynamics (MD) simulation of the cotinine-Abeta interaction was performed. Cotinine stabilized the monomeric form of the peptide and decreased Abeta aggregation. MD simulation of the cotinine/Abeta interaction showed that cotinine interacts with key histidine residues that may affect Abeta aggregation. The behavioral analyses showed that cotinine improves working and reference memory and decreases plaque deposition in the Tg6799 mice. Voltage clamp analysis showed that cotinine is a selective positive allosteric modulator of the alpha7-nAChR. Cotinine reduces Abeta aggregation, improves memory and reduces amyloid burden in the Tg6799 mice. Cotinine is a selective positive allosteric modulator of the alpha7-nAChR.