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.

Neuroinflammation in a Mouse Model of Alzheimer’s Disease versus Auditory Dysfunction: Machine Learning Interpretation and Analysis

“…In the MGB of APP/PS1 mice, similar to the IC, the microglia density increase was not signi cant (Figure 3A top panel; B, left graph). The CD68+ microglia proportion showed a signi cant increase in this genotype (Figure 3A middle panel; B right graph), even though signi cant levels amyloid-β plaque was not detected in our previous assay (Na et al, 2023). With the higher resolution images presented here, it is clear that the CD68+ cells are associating with the low levels of plaque present (Figure 3).…”

“…Multiple lines of evidence suggested that neuroin ammation might be the link between AD and the central auditory hyperactivity in 5xFAD mice. First, we previously performed a comprehensive examination on amyloid-b plaque deposition in the central auditory system of the 5xFAD mice, and found that amyloid-b plaque was prominent in the upper auditory brainstem of 5xFAD mice (Na et al, 2023).…”

“…The difference in freezing scores between the novel session and tone test session demonstrated that 5xFAD mice were successfully trained (Figure 8). The insigni cant change of ABR threshold in 5xFAD mice at 6M (Na et al, 2023) suggests that impaired performance of those mice in this test was not due to the inability to detect the auditory cue. However, whether this de cit was due to amygdala dysfunction should be interpreted carefully.…”

“…ABR peaks and troughs were registered by a reviewer blinded to the experimental design and mouse genotypes as described (Na et al, 2023). Wave latency was de ned as the difference between auditory stimuli onset (0 ms) to the time of the peak apex (ms).…”

Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models

“…However, much of this characterization is performed later in disease progression, not capturing functional changes at earlier disease points preceding synapse loss [104,105]. Molecular and functional investigation that has been carried out in early to mid-disease mostly consists of swiftly-progressing genetic models of AD that preclude the use of littermate controls [36][37][38][39][40][41][42]. To detect and systematically investigate mechanisms of compensatory plasticity, it is essential to use a well-charted model with appropriately-matched non-transgenic controls.…”