Activation of Wnt/β‐catenin signaling by lithium chloride attenuates d‐galactose‐induced neurodegeneration in the auditory cortex of a rat model of aging

• Published in: FEBS open bio Vol. 7; no. 6; pp. 759 - 776
• Main Authors: Xia, Ming‐Yu, Zhao, Xue‐Yan, Huang, Qi‐Lin, Sun, Hai‐Ying, Sun, Chen, Yuan, Jie, He, Chang, Sun, Yu, Huang, Xiang, Kong, Wen, Kong, Wei‐Jia
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2017; John Wiley and Sons Inc
• Subjects: Age; Aging; Alzheimer's disease; Apoptosis; auditory cortex; Auditory system; Bmi1; Catenin; Cell cycle; Cortex (auditory); Deoxyribonucleic acid; DNA; Galactose; Genetic testing; Hearing loss; INK4a protein; Kinases; Lithium; Lithium chloride; Localization; Lymphoma; Mitochondrial DNA; Neurodegeneration; p16 Protein; p53 Protein; Pathogenesis; Phosphorylation; presbycusis; Proteins; Signal transduction; Statistical analysis; Therapeutic applications; Wnt protein; Wnt/β‐catenin signaling; Wnt/β‐catenin signaling; auditory cortex; aging; presbycusis; Bmi1
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12220

Degeneration of the central auditory system, which is characterized by reduced understanding of speech and source localization of sounds, is an important cause of age‐related hearing loss (presbycusis). Accumulating evidence has demonstrated that Wnt/β‐catenin signaling plays an essential role in the development of the auditory system but its potential role in presbycusis remains unclear. In this study, we used a rat model of aging, created by chronic systemic exposure to d‐galactose (d‐gal), and explored changes in Wnt/β‐catenin signaling in the auditory cortex. A decrease in Wnt/β‐catenin signaling in the auditory cortex was found in both naturally aging and d‐gal‐mimetic aging rats, as indicated by increased GSK3β activity and decreased β‐catenin activity. Moreover, lithium chloride (Licl), an activator of Wnt signaling pathway, was administered long term to 15‐month‐old d‐gal‐treated rats. Activation of Wnt/β‐catenin signaling by Licl attenuated d‐gal‐induced auditory cortex apoptosis and neurodegeneration. Bmi1, a transcription factor implicated in antiaging and resistance to apoptosis, can be modulated by β‐catenin activity. Here, we showed that the expression of Bmi1 was reduced and the expression of its downstream genes, p16INK4a, p19Arf, and p53 were increased in the auditory cortex both of naturally aging and d‐gal‐mimetic aging rats. In addition, Licl significantly increased Bmi1 expression and reduced p16INK4a, p19Arf, and p53 expression. Our results indicated that decreased Wnt/β‐catenin signaling might participate in the pathogenesis of central presbycusis through modulating the expression of Bmi1. Wnt/β‐catenin signaling might be used as a potential therapeutic target against presbycusis. Degeneration of the central auditory system is an important cause of age‐related hearing loss (presbycusis). This study explored the possible role of Wnt/β‐catenin signaling in neuronal survival in the auditory cortex during aging using a rat model of aging. Our results indicated that decreased Wnt/β‐catenin signaling might participate in the pathogenesis of presbycusis by modulating the expression of Bmi1. Wnt/β‐catenin signaling might be used as a potential therapeutic target against presbycusis.