Abstract
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, p16 INK 4a, p19 Arf, 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 p16INK 4a, 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.
Highlights
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
We used a rat model of aging, created by chronic systemic exposure to D-galactose (D-gal), and explored changes in Wnt/b-catenin signaling in the auditory cortex
A decrease in Wnt/b-catenin signaling in the auditory cortex was found in both naturally aging and D-gal-mimetic aging rats, as indicated by increased glycogen synthase kinase 3b (GSK3b) activity and decreased b-catenin activity
Summary
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). A decrease in Wnt/b-catenin signaling in the auditory cortex was found in both naturally aging and D-gal-mimetic aging rats, as indicated by increased GSK3b activity and decreased b-catenin activity. We showed that the expression of Bmi 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. Abbreviations AHL, age-related hearing loss; Bmi, B lymphoma Mo-MLV insertion region 1; CD, common deletion; Cyclin D1, cell cycle protein D1; D-gal, D-galactose; GSK3b, glycogen synthase kinase 3b; Licl, Lithium chloride; LSCM, laser-scanning confocal microscope; mtDNA, mitochondrial DNA; PBS, phosphate-buffered saline; TCF/LEF, T-cell factor/lymphoid enhancer-binding factor; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine 50-triphosphate nick-end labeling. The molecular mechanisms involved in central presbycusis remain elusive
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