β-Secretase BACE1 Is Required for Normal Cochlear Function | JoVE Visualize

Area of Science:

Neuroscience
Auditory Physiology
Alzheimer's Disease Research

Background:

Beta-site cleaving enzyme 1 (BACE1) is a key enzyme in amyloid precursor protein (APP) cleavage, linked to Alzheimer's disease (AD) pathogenesis.
BACE1's role in normal physiological functions beyond AD is not fully understood, necessitating investigation into its broader biological roles.
Understanding BACE1's diverse functions is critical for evaluating the safety and efficacy of BACE1 inhibitors for AD treatment.

Purpose of the Study:

To investigate the role of BACE1 in auditory function and identify the underlying mechanisms of hearing deficits in BACE1-deficient mice.
To determine if pharmacological inhibition of BACE1 in adult mice recapitulates the hearing loss observed in BACE1 knockout models.
To elucidate the developmental impact of BACE1 deficiency on cochlear structure and auditory nerve function.

Main Methods:

Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were used to assess hearing function in BACE1 knockout (BACE1-/-) mice and wild-type littermates.
Immunohistochemistry was employed to examine cochlear and auditory nerve pathology, including synaptic organization and myelination.
Adult wild-type mice were treated with a BACE1 inhibitor (NB-360) to assess the effects of pharmacological BACE1 suppression on hearing and cochlear integrity.

Main Results:

BACE1-/- mice exhibited significant hearing deficits, characterized by elevated ABR thresholds and reduced DPOAE amplitudes.
Neuropathological findings in BACE1-/- mice included aberrant synaptic organization in the cochlea, hypomyelination of auditory nerve fibers, and disorganized spiral ganglion neuron (SGN) fibers.
Pharmacological BACE1 inhibition in adult wild-type mice did not impair hearing or induce cochlear abnormalities, indicating the observed deficits in knockout mice are developmental.

Conclusions:

BACE1 is essential for normal auditory function, with its absence leading to hearing loss primarily due to developmental defects in cochlear myelination and synaptic organization.
The hearing impairment in BACE1 knockout mice represents a developmental phenotype, distinct from the potential effects of acute BACE1 inhibition in adulthood.
These findings highlight a critical physiological role for BACE1 in auditory system development and inform the therapeutic strategies for Alzheimer's disease involving BACE1 inhibitors.