Determinants of age-induced hearing loss and reversal strategies (Generation of auditory system-specific Alzheimer's Disease models)

University Of Nevada Reno, Reno NV

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Abstract

Abstract Hearing loss (HL) and neurosensory loss are potential hazard for Alzheimer's disease (AD) and incident all-cause dementia; however, no direct evidence exists to implicate HL as a harbinger for AD. Identification of sensory deficits, their etiologies, and underlying mechanisms, would undoubtedly be the rehearsal for early intervention of AD. Moreover, cognitive tests in AD patients that uses auditory stimuli should not be confounded by hearing dysfunction. AD mouse models showed hearing dysfunction at, or prior to the debut of mild cognitive impairment (MCI). What is unknown is the unequivocal mechanistic link between HL and AD, using mouse models with appropriate genetic background to allow segregation between age-related hearing loss (ARHL) and AD-related HL. By convention, most if not all, genetic mouse lines used for biological experiments, and in particular, AD models are on C57/B6-Black Swiss background or related lines. Previous studies have demonstrtaed that several mouse lines, including the conventional lines, exhibit early-onset progressive ARHL. This caveat masks the ?slow? or late onset progressive HL that is comparable to HL seen in humans. In contrast, the CBA CaJ strain has a relatively slow rate of ARHL and exhibit a time course similar to humans, after mean lifespan adjustment. Multiple conditional and inducible mouse lines have been generated and have served as powerful tools to study AD mechanisms. In this supplementary study we propose to backcross, at least six conditional/inducible AD mouse lines unto CBA CaJ background and to perform initial auditory test (using auditory brainstem response, ABR, distortion product otoacoustic emissions, DPOAE). Additionally, we will perform histological studies to establish auditory studies appropriate lines, that will facilitate interest in determining the mechanisms of HL in AD models. Our laboratory will also serve as a hub and resource for multiple laboratories, nationwide, interested in sensory deficit associated mechanisms in AD. To ensure long-term benefits to the scientific community, we also propose to cryopreserve the AD models we generate in case of future and or accidental elimination of the lines. The Specific Aims of the proposal are to; 1) Establish, backcrossed, breed, maintain, and distribute, at least six CBA-CaJ-specific AD-conditional and inducible mouse lines. 2) Perform ABR and DPOAE tests to examine auditory functions in the mouse lines. 3) Cryopreserve the critical lines we generate in case of a disaster (e.g. natural disaster, infection).