Nicotine-mediated effects in neuronal and mouse models of synucleinopathy

Mohamed Bilal Fares; Omar Alijevic; Stephanie Johne; Cassia Overk; Makoto Hashimoto; Athanasios Kondylis; Anthony Adame; Remi Dulize; Dariusz Peric; Catherine Nury; James Battey; Emmanuel Guedj; Nicolas Sierro; Damian Mc Hugh; Edward Rockenstein; Changyoun Kim; Robert A Rissman; Julia Hoeng; Manuel C Peitsch; Eliezer Masliah; Carole Mathis

doi:10.3389/fnins.2023.1239009

Nicotine-mediated effects in neuronal and mouse models of synucleinopathy

Front Neurosci. 2023 Aug 31:17:1239009. doi: 10.3389/fnins.2023.1239009. eCollection 2023.

Authors

Mohamed Bilal Fares¹, Omar Alijevic¹, Stephanie Johne¹, Cassia Overk², Makoto Hashimoto², Athanasios Kondylis¹, Anthony Adame², Remi Dulize¹, Dariusz Peric¹, Catherine Nury¹, James Battey¹, Emmanuel Guedj¹, Nicolas Sierro¹, Damian Mc Hugh¹, Edward Rockenstein², Changyoun Kim², Robert A Rissman², Julia Hoeng¹, Manuel C Peitsch¹, Eliezer Masliah², Carole Mathis¹

Affiliations

¹ PMI R&D, Philip Morris Products S.A., Neuchâtel, Switzerland.
² Department of Neurosciences, University of California, San Diego, San Diego, CA, United States.

Abstract

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.

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