Auditory neuronal degeneration in an ahl-corrected mouse model of Alzheimer's disease

摘要

Abstract Alzheimer's disease (AD) is the most common cause of age-related dementia. The pathological changes of AD are well defined and characterized by amyloid β protein (Aβ) in senile plaques (SP) and microtubule-associated protein tau (MAPT) in neurofibrillary tangles (NFTs). A precursor protein (APP) mutations are linked to early- onset familial AD, establishing a link between development of senile plaque pathology and AD. However, currently there are no treatments or preventative strategies for AD available, owed largely to the lack of a comprehensive understanding of the precise molecular mechanisms for earlier detection. We will extend our investigation to early-onset familial AD (FAD) in a novel animal model for this supplement proposal. Evidence from case-controlled and longitudinal population-based studies has established a strong correlation between age-related hearing loss (ARHL) and cognitive impairment and dementia. No evidence exists showing a specific link between AD and auditory deficits, especially a mechanistic link. In collaboration with Dr. Sambamurti, we recently developed an Ahl-corrected FAD mouse model expressing FAD mutations of APP and PSEN1, referred to as FADc/c mice. This strategy eliminated the known genetic Ahl accelerated age-related hearing loss (ARHL) mutation, uncovering AD-pathology-mediated hearing deficits. Our preliminary results show that both female and male FADc/c mice on a C57BL/6J strain background have significantly higher auditory thresholds measured at 8, 16, and 32 kHz at the age of 9–10 months compared to wild-type (WTc/c) mice with almost 90% of females and 40% of males showing severely elevated thresholds above 60 dB SPL. Our preliminary results also show that the extent of amyloid deposition in the hippocampus of FADc/c mice correlates with the severity of hearing loss when assessed at the age of 9–10 months. Based on our preliminary experimental data and literature suggesting that amyloid pathology can induce auditory impairment in animal models, we will test our hypothesis that neurodegenerative pathways triggered by FAD mutations promote auditory nerve dysfunction. An extension of this hypothesis is to evaluate hearing loss as a functional biomarker for AD in those with a predisposition. Additionally, one recent study indicated that moderate noise exposure accelerates cognitive decline in a triple transgenic mouse model. Thus we will further test whether environmental insults to the auditory system, such as noise-induced hidden hearing loss, may hasten cognitive decline in those with predisposition to AD via a combination of stress and AD-mediated inflammation. In summary, our proposal will assess the effects of FAD mutations in APP and PS1 on hearing loss in Ahl-corrected transgenic mice. Furthermore, we will assess whether environmental factors, such as moderate noise exposure, in mice with predisposition for AD accelerate cognitive decline. The results may provide insight into a timeframe that would allow for intervention.