Nicotine-mediated effects in neuronal and mouse models of synucleinopathy.
induced pluripotent stem cell (iPSC)
neuroprotection
nicotine
nicotinic acetylcholine receptors (nAChR)
synucleinopathy
transgenic mice
Journal
Frontiers in neuroscience
ISSN: 1662-4548
Titre abrégé: Front Neurosci
Pays: Switzerland
ID NLM: 101478481
Informations de publication
Date de publication:
2023
2023
Historique:
received:
12
06
2023
accepted:
08
08
2023
medline:
18
9
2023
pubmed:
18
9
2023
entrez:
18
9
2023
Statut:
epublish
Résumé
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
Identifiants
pubmed: 37719154
doi: 10.3389/fnins.2023.1239009
pmc: PMC10501483
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1239009Informations de copyright
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.
Déclaration de conflit d'intérêts
OA, SJ, AK, RD, DP, CN, JB, EG, NS, DM, and CM are employees of Philip Morris International. MP was a PMI employee at the time of the study and is now retired. JH was a PMI employee at the time of the study and is now an employee of Vectura Fertin Pharma. MF was a PMI employee at the time of the study and is now a co-founder and director of R&D at ND Biosciences, a company developing next-generation therapeutics and diagnostics for neurodegenerative diseases. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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