gms | German Medical Science

Introduction: Presbycusis is the main preventable risk factor of Alzheimer disease (AD) in midlife. It is necessary to investigate mechanistic links between both conditions. We use genetically modified (knock in) mouse models reproducing the beta-amyloid proteinopathy of human AD [1] with presbycusis traits (i.e., hearing loss starting in the high frequencies at six months), due to their C57BL6/J genetic background. Thus, they may be powerful tools to unravel pathophysiological connections between both conditions. Our goal is to collect evidence that the beta-amyloid proteinopathy characteristic of AD worsens preexisting presbycusis, thus generating a vicious spiraling between both conditions.

Methods: In APP knock-in mice a genetically modified amyloid precursor protein (APP) gene, inserted in its original locus, leads to pathological processing of APP, with beta-amyloid deposits comparable to those found in human AD. Controls were age-matched wild type (WT) C57BL6/J mice, which develop presbycusis traits at six months. Auditory brainstem response recordings were carried out followed by immunocytochemistry to localize antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and the oxidative stress marker 3-nitrotyrosine (3NT) in cochlear sections, along with the inflammatory markers IL6, TNF-alfa and Iba1.

Results: At 6–8 months of age, WT C57BL6/J mice developed characteristic early high-frequency hearing threshold elevation. Age-matched APP mice had significantly higher thresholds, supporting effects of amyloid pathology on pre-existing presbycusis. With age, threshold elevations were equally higher in both groups. In parallel, in aged APP mice SOD and CAT immunoreactivities were diminished in the cochlea, relative to control C57BL6/J. This was evident in the stria vascularis and spiral ligament, as well as in regions of the spiral limbus, along with spiral ganglion cell bodies. This, along with immunolabeling for the oxidative stress marker 3-NT indicates increased sensitivity to cochlear oxidative stress in APPNL-F mice and matches increased levels of inflammatory markers.

Discussion: Lower immunoreactivity levels of SOD and CAT in the auditory receptor and spiral ganglion of aged APP mice, along with levels of 3-NT, compared with age-matched mice of the C57BL/6J strain, supports diminished antioxidation capacity and exacerbation of oxidative stress in the cochlea of mice carrying traits of AD beta-amyloid proteinopathy. This correlates with increased levels of inflammatory markers, suggesting that altered APP proteostasis in AD affects the peripheral auditory receptor through yet unknown mechanisms, leading to increased oxidative stress and inflammation. If preexisting presbycusis is thus exacerbated, as shown by higher auditory thresholds in 6- to 8-month-old APP mice, this may in turn negatively affect the course of AD, leading to a vicious circle with potentially important clinical implications.