Nicotine-mediated effects in neuronal and mouse models of synucleinopathy

IntroductionAlpha-synuclein (& alpha;-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson's disease. The plant alkaloid nicotine was reported to attenuate & alpha;-Syn aggregation in different models, but its precise mode of action remains unclear.MethodsIn this study, we investigated the effect of 2-week chronic nicotine treatment on & alpha;-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in D-line & alpha;-Syn transgenic mice. We also established a novel humanized neuronal model of & alpha;-Syn aggregation and toxicity based on treatment of dopaminergic neurons derived from human induced pluripotent stem cells (iPSC) with & alpha;-Syn preformed fibrils (PFF) and applied this model to investigate the effects of nicotine and other compounds and their modes of action.Results and discussionOverall, our results showed that nicotine attenuated & alpha;-Syn-provoked neuropathology in both models. Moreover, when investigating the role of nicotinic acetylcholine receptor (nAChR) signaling in nicotine's neuroprotective effects in iPSC-derived dopaminergic neurons, we observed that while & alpha;4-specific antagonists reduced the nicotine-induced calcium response, & alpha;4 agonists (e.g., AZD1446 and anatabine) mediated similar neuroprotective responses against & alpha;-Syn PFF-provoked neurodegeneration. Our results show that nicotine attenuates & alpha;-Syn-provoked neuropathology in vivo and in a humanized neuronal model of synucleinopathy and that activation of & alpha;4 & beta;2 nicotinic receptors might mediate these neuroprotective effects.

Automated summary

This study investigated the effects of nicotine on α-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in transgenic mice and in a human neuronal model of synucleinopathy. The results showed that nicotine attenuated α-Syn-provoked neuropathology in both models. Furthermore, activation of α4β2 nicotinic receptors might mediate these neuroprotective effects.