Nicotine-mediated effects in neuronal and mouse models of synucleinopathy

Frontiers in Neuroscience

Neuroscience

Anthony Adame¹  Eliezer Masliah¹  Robert A. Rissman¹  Makoto Hashimoto¹  Edward Rockenstein¹  Cassia Overk¹  Changyoun Kim¹  Mohamed Bilal Fares²  Stephanie Johne²  Julia Hoeng²  Manuel C. Peitsch²  Emmanuel Guedj²  Dariusz Peric²  Carole Mathis²  Athanasios Kondylis²  Catherine Nury²  James Battey²  Nicolas Sierro²  Remi Dulize²  Omar Alijevic²  Damian Mc Hugh² 

[1] Department of Neurosciences, University of California, San Diego, San Diego, CA, United States;PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland;

关键词: synucleinopathy;    induced pluripotent stem cell (iPSC);    transgenic mice;    nicotine;    nicotinic acetylcholine receptors (nAChR);    neuroprotection;   

DOI  :  10.3389/fnins.2023.1239009

 received in 2023-06-12, accepted in 2023-08-08,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionAlpha-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.MethodsIn 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 discussionOverall, 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.

【 授权许可】

Unknown   
Copyright © 2023 Fares, Alijevic, Johne, Overk, Hashimoto, Kondylis, Adame, Dulize, Peric, Nury, Battey, Guedj, Sierro, Mc Hugh, Rockenstein, Kim, Rissman, Hoeng, Peitsch, Masliah and Mathis.