Nicotine prevents in vivo Aβ toxicity in Caenorhabditis elegans via SKN-1

Objective: Nicotine, a main active compound in tobacco, has been shown to attenuate amyloid-beta (A beta) mediated neurotoxicity. However, the detailed underlying mechanisms remains to be elucidated. In this study, nematode Caenorhabditis elegans (C. elegans) had been chosen as the model animal for dissecting the role of nicotine in the prevention of A beta-induced toxicity in vivo. Methods: CL2120 and CL4176 transgenic worms of Alzheimer's disease (AD) models were treated with different concentrations of nicotine, and worm paralysis was monitored. Next, the effects of nicotine on A beta deposits, A beta oligomers, reactive oxygen species (ROS) and the oxidative stress resistance in worms were measured. Moreover, the pathway responsible for nicotine alleviating A beta-induced toxicity in vivo was explored by observing the oxidative stress resistance of skn-1 or daf-16 mutants in the presence of nicotine. Furthermore, the worm paralysis and A beta deposits were further checked in CL4176 worms with skn-1 RNA interference under the condition of nicotine. Results: Nicotine (5 mu M) attenuated AD-like symptoms of worm paralysis in CL2120 and CL4176 transgenic C. elegans. Nicotine did not inhibit A beta aggregation in vitro, however it suppressed A beta deposits and reduced the A beta oligomers to alleviate the toxicity induced by A beta overexpression in C. elegans. Although nicotine did not possess apparent intrinsic anti-oxidative activity, it decreased in vivo reactive oxygen species (ROS). Nicotine enhanced the oxidative stress resistance of C. elegans, which was mediated by SKN-1 but not DAF-16 signaling. Furthermore, skn-1 RNAi abrogated the effect of nicotine reducing A beta deposits in vivo and completely blocked nicotine preventing A beta induced worm paralysis. Conclusions: Nicotine reduces A beta oligomer formation and alleviates A beta-induced paralysis of C. elegans, which is mediated by SKN-1 signaling.

Automated summary

Nicotine reduces Aβ oligomer formation and alleviates Aβ-induced paralysis of C. elegans, primarily by lowering Aβ deposits and reducing Aβ oligomers. Additionally, nicotine enhances oxidative stress resistance in worms through SKN-1 signaling.