TDP43/HDAC6/Prdx1 signaling pathway participated in the cognitive impairment of obstructive sleep apnea via regulating inflammation and oxidative stress

• Published in: International immunopharmacology Vol. 127; p. 111350
• Main Authors: Ou, Yanru, Shen, Chong, Chen, Zhifeng, Liu, Ting, Peng, Yating, Zong, Dandan, Ouyang, Ruoyun
• Format: Journal Article
• Language: English
• Published: Netherlands 25.01.2024
• Subjects: Oxidative stress; TDP-43; Prdx1; Cognitive; Inflammation; Obstructive sleep apnea; HDAC6
• DOI: 10.1016/j.intimp.2023.111350
• ISSN: 1567-5769; 1878-1705

Neuroinflammation and oxidative stress induced by intermittent hypoxia (IH) are associated with cognitive dysfunction in patients with obstructive sleep apnea (OSA). Recently, TAR DNA-binding protein 43 (TDP-43), histone deacetylase 6 (HDAC6), and peroxiredoxin 1 (Prdx1) have been reported to be involved in cognitive impairment in many degenerative diseases; however, the underlying mechanisms remain unclear. In the present study, subjects underwent polysomnography to diagnose OSA. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) and peripheral blood samples were collected. HMC3 cells were treated with lipopolysaccharide (LPS) to mimic in vitro neuroinflammation. Western blotting was used to assess protein expression and ELISA to assess inflammation and oxidative stress levels. Participants were divided into three groups: healthy control (n = 20); mild to moderate OSA (n = 20); and severe OSA (n = 20). The MoCA scores in mild-moderate OSA and severe OSA were lower than those in healthy controls. Continuous positive airway pressure therapy was found to be effective for cognitive impairment in subjects with severe OSA (24.70 ± 1.81). Expression of TDP-43 and HDAC6 was increased in subjects with OSA, whereas Prdx1 expression was decreased. Alterations in these proteins were partially reversed after 12 weeks of CPAP treatment. Protein expression of TDP-43 and HDAC6 was negatively correlated with MoCA scores in patients with OSA, while Prdx1 expression exhibited the opposite trend. In LPS-treated HMC3 cells, TDP-43 and HDAC6 were upregulated, whereas Prdx1 expression was reduced. TDP-43 influenced the expression of Prdx1 by regulating HDAC6, and inflammation and oxidative stress varied with the expression of TDP-43. When a specific inhibitor of HDAC6 was used, LPS-induced inflammation and oxidative stress were alleviated by an elevated level of Prdx1. In summary, findings of the present study suggest that TDP-43 influenced Prdx1 by regulating HDAC6 expression and promoting neuroinflammation and oxidative stress. This process may be involved in the cognitive impairment experienced by patients with OSA and may provide potential therapeutic targets.