Early-Onset Hearing Loss in Mouse Models of Alzheimer’s Disease and Increased DNA Damage in the Cochlea

There is considerable interest in whether sensory deficiency is associated with the development ofAlzheimer’s disease (AD). Notably, the relationship between hearing impairment and AD is of high relevancebut still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgADand 3xTgAD/Polβ+/−. The 3xTgAD/Polβ+/− mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes.The ABR thresholds were significantly higher in 3xTgAD/Polβ+/− mice than in 3xTgAD mice at 16 kHz, anddistortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factorunderlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex.Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner haircells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulatedin the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findingsprovide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damagein the cochlea might contribute to the development of early hearing loss in AD.