Nicotine-mediated effects in neuronal and mouse models of synucleinopathy

• Published in: Frontiers in neuroscience 2023-08, Vol.17, p.1239009-1239009
• Main Authors: Fares, Mohamed Bilal, Alijevic, Omar, Johne, Stephanie, Overk, Cassia, Hashimoto, Makoto, Kondylis, Athanasios, Adame, Anthony, Dulize, Remi, Peric, Dariusz, Nury, Catherine, Battey, James, Guedj, Emmanuel, Sierro, Nicolas, Mc Hugh, Damian, Rockenstein, Edward, Kim, Changyoun, Rissman, Robert A, Hoeng, Julia, Peitsch, Manuel C, Masliah, Eliezer, Mathis, Carole
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (nicotinic); Animal models; Antibodies; Antigens; Brain; Dopamine receptors; Fibrils; induced pluripotent stem cell (iPSC); Inflammation; Laboratories; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neurons; Neuroprotection; Neuroscience; Neurotoxicity; Nicotine; nicotinic acetylcholine receptors (nAChR); Parkinson's disease; Pathology; Pluripotency; Proteins; Synuclein; synucleinopathy; Tobacco; Toxicity; Transgenic mice
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2023.1239009

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. 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. 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 and in a humanized neuronal model of synucleinopathy and that activation of α4β2 nicotinic receptors might mediate these neuroprotective effects.