Expression of amyloid-β in mouse cochlear hair cells causes an early-onset auditory defect in high-frequency sound perception

Abstract

Increasing evidence indicates that defects in the sensory system are highly correlated with age-related neurodegenerative diseases, including Alzheimer's disease (AD). This raises the possibility that sensory cells possess some commonalities with neurons and may provide a tool for studying AD. The sensory system, especially the auditory system, has the advantage that depression in function over time can easily be measured with electrophysiological methods. To establish a new mouse AD model that takes advantage of this benefit, we produced transgenic mice expressing amyloid-β (Aβ), a causative element for AD, in their auditory hair cells. Electrophysiological assessment indicated that these mice had hearing impairment, specifically in high-frequency sound perception (>32 kHz), at 4 months after birth. Furthermore, loss of hair cells in the basal region of the cochlea, which is known to be associated with age-related hearing loss, appeared to be involved in this hearing defect. Interestingly, overexpression of human microtubule-associated protein tau, another factor in AD development, synergistically enhanced the Aβ-induced hearing defects. These results suggest that our new system reflects some, if not all, aspects of AD progression and, therefore, could complement the traditional AD mouse model to monitor Aβ-induced neuronal dysfunction quantitatively over time.

Reduced acoustic startle response and peripheral hearing loss in the 5xFAD mouse model of Alzheimer's disease

“…; Bowl & Dawson 2015;Fetoni et al 2011;Parham et al 2001). Indeed, previous studies have noted the development of A plaques within the brainstem of 5xFAD mice, although at lower levels than hippocampus and cortex (Oakley et al 2006;Ohno et al 2007) and the reduced acoustic startle response in 5xFAD mice may be due to dysfunction within these brain regions or due to A -induced axonopathy within motoneurons of the spinal cord (Jawhar et al 2012) or cochlear hair cells (Omata et al 2016). Further research is therefore needed to characterize neuropathology within brain regions mediating the acoustic startle response and ABR in the 5xFAD mice (Brown et al 2008;Willaredt et al 2014).…”

“…The mechanism for this hair cell loss is unknown, but could involve loss of trophic support to hair cells owing to reduced connections with afferent nerves, given evidence of decreases in postsynaptic markers in the 5xFAD brain (Oakley et al 2006). Furthermore, Omata et al (2016) have shown auditory deficits for high frequency clicks (32 kHz) and excessive loss of hair cells in Tg(Math1 E -AB42)1Lt mice, which express A within cochlear hair cells, suggesting that A may induce peripheral hearing dysfunction in 5xFAD mice. Alternatively, hair cell loss may involve increased intracellular Notch signaling, given that PS1 comprises part of the -secretase complex, which is known to cleave the Notch transmembrane protein, and initiate the Notch signaling cascade (De Strooper et al 1999).…”

“…Genetically modified mouse models are central to understanding the neurogenetic bases of both hearing (Brown et al 2008) and neurodegenerative disorders and for the discovery of new treatments for those disorders (Jucker 2010;Peters et al 2007). Many mouse models of AD are available (Bales 2012;Chin 2011;Webster et al 2014), and it has been shown that expression of mutant amyloid beta in cochlear hair cells causes auditory deficits in one mouse model of AD (Omata et al 2016). Current data on hearing ability in most AD models are limited to behavioral measures of auditory ability such as the auditory startle response (ASR), in which AD models typically show normal (Tg2576 and APP swe /PS1 M164L ) or exaggerated (3xTg AD and CRND8) startle responses (McCool et al 2003;Pietropaolo et al 2008Pietropaolo et al , 2012Wang et al 2012).…”

The hidden variables problem in Alzheimer's disease clinical trial design

“…Omata et al. demonstrated that the auditory system may be similarly susceptible by observing significant hearing impairments in a transgenic mouse model expressing Aβ in cochlear hair cells [39]. Hearing and sight are requisite for evaluations of cognition, which rely directly on the responses to either auditory or visual stimuli.…”

“…Koronyo-Hamaoui et al and others have recently clarified that protein misfolding may be directly responsible for this decline, observing Ab accumulation in the eyes of multiple AD mouse models and in postmortems of AD patients [36,38]. Omata et al demonstrated that the auditory system may be similarly susceptible by observing significant hearing impairments in a transgenic mouse model expressing Ab in cochlear hair cells [39]. Hearing and sight are requisite for evaluations of cognition, which rely directly on the responses to either auditory or visual stimuli.…”