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5XFAD mice show early-onset gap encoding deficits in the auditory cortex.

ABSTRACT: Early detection will be crucial for effective treatment or prevention of Alzheimer's disease. The identification and validation of early, noninvasive biomarkers is therefore key to avoiding the most devastating aspects of Alzheimer's disease. Measures of central auditory processing such as gap detection have recently emerged as potential biomarkers in both human patients and the 5XFAD mouse model of Alzheimer's disease. Full validation of gap detection deficits as a biomarker will require detailed understanding of the underlying neuropathology, including which brain structures are involved and how the operation of neural circuits is affected. Here we show that 5XFAD mice exhibit gap detection deficits as early as 2 months of age, well before development of Alzheimer's disease-associated pathology. We then examined responses of neurons in the auditory cortex to gaps in white noise. Both gap responses and baseline firing rates were robustly and progressively degraded in 5XFAD mice compared to littermate controls. These impairments were first evident at 2-4 months of age in males, and 4-6 months in females. This demonstrates early-onset impairments to the central auditory system, which could be due to damage in the auditory cortex, upstream subcortical structures, or both.

SUBMITTER: Weible AP

PROVIDER: S-EPMC7483957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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5XFAD mice show early-onset gap encoding deficits in the auditory cortex.

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