UNRAVELING NEURODEGENERATIVE PATHWAYS AND AUDITORY DEFICITS IN 5XFAD MICE: INSIGHTS INTO AD SENSORY ALTERATIONS

Author

Dheyaa Al-Sallami, Southern Illinois University CarbondaleFollow

Date of Award

12-1-2025

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Tischkau, Shelley

Second Advisor

Rybak, Leonard

Third Advisor

Nie, Daotai

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by loss of functional capacity in cognition and accumulation of amyloid-β (Aβ) in brain regions. Despite extensive research on central amyloid pathology, peripheral sensory impairment, especially hearing loss, has been reported as an early and clinically relevant biomarker of disease onset in recent evidence. Epidemiological research shows hearing loss to precede cognitive symptom onset by several years and elevate dementia risk; however, molecular correlations between central amyloid pathology and auditory loss remain poorly understood. This thesis aims to fill this critical gap by investigating the proposal that Aβ42 translocates from central nervous system to cochlea across cerebrospinal fluid-perilymph exchange and blood-labyrinth barrier failure and causes synaptic disconnection, neuron loss, and hearing loss in 5XFAD mouse model of familial AD.In order to test this hypothesis, an in-depth multimodal strategy was employed, consisting of longitudinal electrophysiological recordings, ultrastructure and high-resolution confocal microscopy, molecular analyses of oxidative and apoptotic stress, and therapeutic interventions. Within five related objectives, this paradigm facilitated an orderly investigation of auditory function, cochlear disease, and mechanism-based pathways over developmental time courses from early to late disease states. Functional measures demonstrated progressive losses of ABR in terms of significant decreases in Wave I amplitude and suprathreshold desynchrony, at times prior to normal reorganization of threshold. These results implied that synaptic deterioration, not loss of hair cells, is an early initiator of auditory decline. Ultrastructural and confocal analyses confirmed progressive accumulation of Aβ₄₂ in spiral ganglion neurons, vasculature of stria, and ribbon synapses, occurring in temporally and spatially coordinated parallel to functional loss. Quantitative measurement of synaptic indicators established an unprecedented pathological process termed "synaptic uncoupling" in which intact pre- and postsynaptic elements became spatially separated, resulting in solitary synaptic entities and directly correlating therewith diminished amplitude in auditory brainstem response (ABR). Molecular studies also established an axis consisting of oxidative stress, mitochondrial impairment, and apoptotic activation, implicating strial marginal cells as particularly vulnerable, and indicating vascular and metabolic impairment as principal contributing causes to pathology. Finally, systemic treatment with the antioxidant epigallocatechin-3-gallate (EGCG) was shown to safeguard auditory function, lower cochlear content of Aβ42, and reverse cell damage, providing proof-of-concept of peripheral therapeutic interventions modulating disease process. In total, these results provide a mechanistic connection between central amyloid overproduction and peripheral auditory failure through anatomical conduits and loss of barrier integrity. The findings recharacterize AD-associated hearing loss as an initial peripheral pathology instead of an indirect consequence of central decline. At the clinical level, increased amplitude of ABR Wave I and suprathreshold synchrony become sensitive, non-intrusive biomarkers for early AD detection, and the characterization of synaptic uncoupling as an exploitable, reversible process identifies new therapeutic potential. Beyond expanding mechanistic knowledge, this study places the cochlea as both an early warning sign and an AD therapeutic target, providing new hope for early detection, treatment, and creation of peripheral therapeutic modalities to support brain-centered therapeutic approaches.