Alzheimer′s disease amyloid pathology correlates with higher auditory thresholds and increased oxidative stress and cochlear inflammation in a mouse model combining presbycusis and Alzheimer′s disease

Presbycusis is the main preventable risk factor of Alzheimer disease (AD). We test the hypothesis that beta-amyloid exacerbates presbycusis, generating a vicious circle between both. We used APPNL-F “knock-in” mice, in which insertion of a mutated amyloid precursor protein (APP) gene induces abnormal APP processing, with beta-amyloid deposits comparable to those of human AD. Controls were wild type C57BL6/J mice (WT) developing presbycusis at six months. ABRs were carried out followed by immunocytochemistry in the cochlea for the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), the oxidative stress marker 3-nitrotyrosine (3NT) and inflammatory markers IL6, TNF-alpha and Iba1. WT mice had high-frequency threshold elevation past 6 months, resembling early stages of presbycusis. Age-matched APP mice had significantly higher thresholds, suggesting effects of amyloid pathology on hearing loss. In correlation, in aged APPNL-Fmice, SOD and CAT were diminished in the cochlea, relative to WT. This, along with labeling for 3-NT indicates increased sensitivity to cochlear oxidative stress in APPNL-F mice, matching increased levels of inflammatory markers. Lower immunoreactivity for SOD and CAT in the cochlea of aged APPNL-F mice, along with levels of 3-NT, compared with age-matched WT, supports diminished antioxidation capacity and exacerbation of oxidative stress in the cochlea of mice with traits of AD proteinopathy. This along with increased inflammatory markers, suggests that AD affects the cochlea through unknown mechanisms. If preexisting presbycusis is thus exacerbated, as shown by higher auditory thresholds in APPNL-F mice, this may in turn negatively affect the course of AD, leading to a vicious circle with potentially important clinical implications.

Supported by Cluster of Excellence “Hearing4all”, EXC 2177/1, ID: 390895286, part of the framework of the Germany’s Excellence Strategy of the German Research Foundation, DFG and by PID2020-117266RB-C22 from AEI, Ministerio de Ciencia e Innovación, Spain.

Publication History

Article published online:
12 May 2023