Peer-Reviewed Publications

    Nicotine-mediated effects in neuronal and mouse models of synucleinopathy

    Fares, M. B.; Alijevic, O.; Johne, S.; Overk, C.; Hashimoto, M.; Kondylis, A.; Adame, A.; Dulize, R.; Peric, D.; Nury, C.; Battey, J.; Guedj, E.; Sierro, N.; Mc Hugh, D.; Rockenstein, E.; Kim, C.; Rissman, R. A.; Hoeng, J.; Peitsch, M. C.; Masliah, E.; Mathis, C.

    Published
    Aug 31, 2023
    DOI
    10.3389/fnins.2023.1239009
    Link to publication
    Topic
    Summary

    Introduction: Alpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson’s disease. The plant alkaloid “nicotine” was reported to attenuate α-Syn aggregation in different models, but its precise mode of action remains unclear.

    Methods: In this study, we investigated the effect of 2-week chronic nicotine treatment on α-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in D-line α-Syn transgenic mice. We also established a novel humanized neuronal model of α-Syn aggregation and toxicity based on treatment of dopaminergic neurons derived from human induced pluripotent stem cells (iPSC) with α-Syn preformed fibrils (PFF) and applied this model to investigate the effects of nicotine and other compounds and their modes of action.

    Results and discussion: Overall, our results showed that nicotine attenuated α-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 α4-specific antagonists reduced the nicotine-induced calcium response, α4 agonists (e.g., AZD1446 and anatabine) mediated similar neuroprotective responses against α-Syn PFF-provoked neurodegeneration. Our results show that nicotine attenuates α-Syn-provoked neuropathology in vivo and in a humanized neuronal model of synucleinopathy and that activation of α4β2 nicotinic receptors might mediate these neuroprotective effects.

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