Hearing loss is an early biomarker in APP/PS1 Alzheimer's disease mice

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive loss of memory and cognitive decline. Over the last decade, it has been found that defects in sensory systems could be highly associated with AD. Hearing is an important neural sense. However, little is known about hearing functional changes in AD. In this study, APP/PS1 AD mice (Jackson Lab: Stack No. 004462) were used. Hearing function was assessed by auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and cochlear microphonics (CM) recordings. Wild-type (WT) littermates served as control. We found that APP/PS1 AD mice measured as ABR threshold had hearing loss. The hearing loss appeared at high frequency as early as 2 months old, prior to the reported occurrence of spatial learning deficit at 6-7 months of age in this AD mouse model. The hearing loss was progressive and extended from high frequency to low frequency. At 3-4 months old, the hearing loss appeared in the whole-frequency range. Moreover, the wave IV and V in the super-threshold ABR were eliminated, indicating substantial impairment in inferior colliculus, nuclei of lateral lemniscus, and medial geniculate body in the upper brainstem. DPOAE in APP/PS1 AD mice was also reduced. However, there was no reduction in CM in APP/PS1 mice. These data demonstrate that unlike age-related hearing loss APP/PS1 AD mice have early onset of hearing loss. These data also suggest that hearing function testing could provide a simple, sensitive, non-invasive screen-tool for early detecting AD and localizing lesion.

Keywords: Age-related hearing loss; Alzheimer’s disease; Auditory brainstem; Auditory brainstem response; Early AD biomarker; Hearing loss; Preclinical AD.

Fig. 1.

Hearing loss in APP/PS1 AD mice. a: ABR waveforms were evoked by click stimulations in WT and APP/PS1 mice. b: Hearing loss in APP/PS1 mice. ABR thresholds were measured by click and tone bursts. Mice were P90 (3 months) old. WT littermates were used as control. *: P<0.05, **: P<0.01 (t test, two-tail).

Fig. 2.

Progressive hearing loss in APP/PS1 AD mice with age. WT littermates were used as control. ABR thresholds were measured by click and tone bursts. Inset at middle upside: A schematic drawing of the time sequence of occurrence of hearing loss and typical AD phenotypes in APP/PS1 AD mice. *: P<0.05, **: P<0.01 (t test, two-tail).

Fig. 3.

Reduction of amplitudes of wave IV-V of ABR in APP/PS1 mice. Mice were P90 (3 months) old. a: Average traces of ABR from APP/PS1 mice (n=10) and WT littermates (n=6). The traces were evoked by a click stimulus at 90 dB SPL and averaged. Bars represent SEM. Wave I-III are produced by the response of the auditory nerve (AN), the cochlear nucleus (CN), and superior olivary complex (SOC), respectively. Wave IV-V are produced by the activity of the inferior colliculus (IC), nuclei of lateral lemniscus (NLL), and medial geniculate body (MGB). b-g: The measured amplitudes of wave I-VI in APP/PS1 and WT mice. There are significant reductions in amplitudes of wave II, IV, V, and VI in APP/PS1 mice. *: P<0.05, **: P<0.01 (t test, two-tail).

Fig. 4.

Reduction of DPOAE in APP/PS1 AD mice. a: Spectrum of acoustic emission recorded from APP/PS1 AD and WT mice. Mice were around P90 (3 months) old. WT littermates served as control. f₀=16 kHz, I₁/I₂=60/55 dB SPL. b: I-O-functions of DPOAE in APP/PS1 AD mice and WT mice. There is significant difference in the I-O functions between APP/PS1 AD mice and WT mice. c: Decrease of DPOAE in APP/PS1 at different frequency. DPOAEs in APP/PS1 AD mice were referred to those in WT mice. *: P<0.05, **: P<0.01 (t test, two-tail).

Fig. 5.

Normal CM in APP/PS1 AD mice. a: CM waveforms in APP/PS1 AD mice and WT mice evoked by 8 kHz tone bursts. b: I-O function of CM recorded from APP/PS1 AD mice and WT mice at P150 (5 months) old. There is no significant difference in the CM IO function between APP/PS1 AD and WT mice.