Increased central auditory gain in 5xFAD Alzheimer's disease mice as an early biomarker candidate for Alzheimer's disease diagnosis

Abstract

Alzheimer's Disease (AD) is a neurodegenerative illness without a cure. All current therapies require an accurate diagnosis and staging of AD to ensure appropriate care. Central auditory processing disorders (CAPDs) and hearing loss have been associated with AD, and may precede the onset of Alzheimer's dementia. Therefore, CAPD is a possible biomarker candidate for AD diagnosis. However, little is known about how CAPD and AD pathological changes are correlated. In the present study, we investigated auditory changes in AD using transgenic amyloidosis mouse models. AD mouse models were bred to a mouse strain commonly used for auditory experiments, to compensate for the recessive accelerated hearing loss on the parent background. Auditory brainstem response (ABR) recordings revealed significant hearing loss, a reduced ABR wave I amplitude, and increased central gain in 5xFAD mice. In comparison, these effects were milder or reversed in APP/PS1 mice. Longitudinal analyses revealed that in 5xFAD mice, central gain increase preceded ABR wave I amplitude reduction and hearing loss, suggesting that it may originate from lesions in the central nervous system rather than the peripheral loss. Pharmacologically facilitating cholinergic signaling with donepezil reversed the central gain in 5xFAD mice. After the central gain increased, aging 5xFAD mice developed deficits for hearing sound pips in the presence of noise, consistent with CAPD-like symptoms of AD patients. Histological analysis revealed that amyloid plaques were deposited in the auditory cortex of both mouse strains. However, in 5xFAD but not APP/PS1 mice, plaque was observed in the upper auditory brainstem, specifically the inferior colliculus (IC) and the medial geniculate body (MGB). This plaque distribution parallels histological findings from human subjects with AD and correlates in age with central gain increase. Overall, we conclude that auditory alterations in amyloidosis mouse models correlate with amyloid deposits in the auditory brainstem and may be reversed initially through enhanced cholinergic signaling. The alteration of ABR recording related to the increase in central gain prior to AD-related hearing disorders suggests that it could potentially be used as an early biomarker of AD diagnosis.

Keywords: Alzheimer’s disease; auditory brainstem response; central auditory gain; central auditory processing disorder; hearing in noise; hearing loss; inhibitory deficit.

Figure 1

5xFAD transgenic mice have increased central gain and hearing loss severity. Auditory test results of (A–F) 5xFAD (red) at 12 months of age (12M) (WT n = 13, 5xFAD n = 15), and (G–J) for APP/PS1 (magenta) at 13M (WT n = 8, APP/PS1 n = 9). (A–J) Corresponding wild-type (WT) littermate data (black). (A) ABR and (B) DPOAE thresholds are expressed as the mean ± SEM. (C–J) Wave I (p1) amplitude, latency, wave IV to I amplitude ratio (p4:p1) and wave I to wave IV interpeak latency of click-evoked ABRs. Asterisks denote significant differences between genotypes: no significance (n.s.), p ≥ 0.05; *p < 0.05; **p < 0.01; and ***p < 0.001.

Figure 2

Auditory functions are normal in 5xFAD mice at an early stage of amyloid deposition. 5xFAD mice (red) and their WT littermates (black). (A) Wave I amplitude, latency, wave IV to I amplitude ratio, wave I to IV interpeak latency (from left to right) of click-evoked ABRs from 5xFAD mice (n = 14) and their WT littermates (n = 9) at 3M. (B–E) Data are expressed as the mean ± SEM. (B) ABR (left) and DPOAE (right) thresholds from 5xFAD mice (n = 11) and their WT littermates (n = 7) at 3M. (C) ABR threshold shift with masking and notched noise for 5xFAD mice (n = 10) and their WT littermates (n = 14) at 3M. (D) ABR and (E) DPOAE threshold shifts at 1 day (1 DPN) and 14 days (14 DPN) post noise exposure for 5xFAD mice (n = 7) and their WT littermates (n = 4) at 3.5M. No significance (n.s.).

Figure 3

Central gain increases prior to central auditory processing disorder in 5xFAD mice. 5xFAD mice (red) and their WT littermates (black). (A,B) The wave I amplitude, latency, wave IV to I amplitude ratio, wave I to IV interpeak latency (from left to right) of click-evoked ABRs from 5xFAD (n = 16) and their WT littermates (n = 14) at (A) 6 M and (B) 9 M. (C,E) ABR (left) and DPOAE (right) thresholds of 5xFAD mice and their WT littermates at (C) 6 M and (E) 9 M. (D,F) ABR threshold shifts with masking (left) and notched noise (right) for 5xFAD mice and their WT littermates at (D) 6 M (5xFAD, n = 10; WT, n = 7) and (F) 12 M (5xFAD, n = 4; WT, n = 8). (C–F) Data are expressed as the mean ± SEM. Asterisks denote the significant differences between genotypes: no significance (n.s.), p ≥ 0.05; *p < 0.05; **p < 0.01; and ***p < 0.001.

Figure 4

Increased central gain in 5xFAD mice is diminished after donepezil treatment. The wave IV to I amplitude ratio of click-evoked ABRs from 5xFAD mice (n = 6) and their WT littermates (n = 4) before (Pre, yellow 5xFAD, gray WT) and after (Post, red 5xFAD, black WT) donepezil treatment. Asterisks denote the significant differences between genotypes: no significance (n.s.), p ≥ 0.05; *p < 0.05; **p < 0.01; and ***p < 0.001.

Figure 5

Differential amyloid plaque accumulation in the central auditory pathway of 5xFAD mice compared to APP/PS1 mice correlates temporally with the onset of central gain. Coronal sections from 13 M wild-type, 3 M 5xFAD, 6 M 5xFAD, 12 M 5xFAD, and 13 M APP/PS1 mice harboring important auditory nuclei were stained with anti-amyloid antibody (A–C, 5× images, yellow) and counterstained with Neurotrace to reveal nuclei (A–C, green). (A) Sections containing hippocampal subiculum (1, Sub), CA1 region (2), auditory cortex (3, AC) and the medial geniculate body (4, MGB) are compared. Regions are indicated with white outlines. (B) Sections containing the inferior colliculus (5, IC) the superior olivary complex (6, SOC) and the medial nucleus of the trapezoid body (7, MNTB) are compared. (C) Sections containing the cochlear nucleus (8, CN) are compared. All scale bars are 1,000 microns. (D) The percent area for each region that is covered with plaque is displayed (n = 6). Data are presented by modified box plots with jitter points represent individual animals. Asterisks denote the significant differences between genotypes: no significance (n.s.). p ≥ 0.05; *p < 0.05; **p < 0.01; and ***p < 0.001.