Objective: This study aims to explore the neuroprotective role of α7 nicotinic acetylcholine receptor (α7nAChR) in mitochondrial homeostasis and its potential as a therapeutic target for Parkinson’s disease (PD) in iPSC-derived neuronal models.

Background: An increasing burden of chronic morbidities imposes major challenges on aging societies. Among those conditions are neurodegenerative diseases, with PD being a primary example, where persistent inflammatory processes contribute to neuronal degeneration. The cholinergic anti-inflammatory pathway (CAP) is gaining recognition as a potential therapeutic target in neurodegenerative diseases. Acetylcholine (ACh) interacts with nAChRs to mediate its effects. The α7nAChR, a key mediator of ACh’s anti-inflammatory properties, has been studied in peripheral immune cells and initial studies in mouse models. However, its role in PD and iPSC-derived neuronal models remains largely unexplored.

Method: We used iPSC-derived neuronal precursors, along with SH-SY5Y cells, to examine the effects of α7nAChR stimulation in a PD-relevant model. Cells were treated with 6-hydroxydopamine (6OHDA) to induce neurotoxicity, in combination with a specific α7nAChR activation. First, we assessed α7nAChR ability to mitigate cell death after 6OHDA treatment. Then, mitochondrial function was evaluated using assays for mitochondrial quality control, apoptosis markers, and mitochondrial DNA (mtDNA) and Cytochrome C release.

Results: Our findings demonstrate that α7nAChR stimulation confers neuroprotection against 6OHDA-induced cytotoxicity in iPSC-derived neuronal precursors and SH-SY5Y cells. Activation of α7nAChR improves mitochondrial integrity and function while reducing apoptosis. Notably, α7nAChR stimulation prevents the release of mtDNA and Cytochrome C, suggesting a role in preserving mitochondrial homeostasis and exerting antiapoptotic effects.

Conclusion: These results highlight the potential of targeting α7nAChR as a novel therapeutic strategy for PD. By preserving mitochondrial function and promoting neuronal survival, α7nAChR activation may offer a promising avenue for neuroprotection in PD and related neurodegenerative disorders.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-%ce%b17-nicotinic-acetylcholine-receptor-in-mitochondrial-homeostasis-and-neuroprotection/