# ROLE OF THE INNATE IMMUNE SYSTEM IN THE SURVIVAL OF AUDITORY NEURONS

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $404,322

## Abstract

Numerous clinical studies have suggested a link between loss of sensory function in the inner ear and the
development of Alzheimer’s disease, but the biological basis of this association is not clear. The
neurodegeneration that occurs in Alzheimer’s disease (AD) is thought to be caused by aberrant processing and
clustering of protein fragments derived from amyloid precursor protein (APP) and the microtubule-associated
protein Tau. Certain identified mutations in APP and Tau are also known to greatly increase the risk of developing
AD. The study of AD-related degeneration in mouse models presents certain challenges. Because of small
differences in the sequences of AD-associated genes in humans vs. rodents, mice do not normally develop AD-
like neurodegeneration. However, a number of transgenic knock-in lines that express human forms of these AD-
associated gene mutations have been created, facilitating the study of amyloid- and Tau-mediated pathology.
We are requesting an administrative supplement to our R01 grant, “Role of the Innate Immune System in the
Survival of Auditory Neurons”, in order to test for cellular degeneration in the inner ears and auditory brainstem
nuclei of a widely-used mouse model of Alzheimer’s disease. Our pilot data show that both APP and Tau are
highly expressed by hair cells and afferent neurons of the inner ear, raising the possibility that mutated forms of
these proteins might promote age-related loss of hearing and balance function. It is further possible that the loss
of sensory function in such mice makes neurons of the CNS more susceptible to AD pathology and degeneration.
One set of proposed experiments will examine whether there is increased loss of spiral ganglion and vestibular
ganglion neurons in AD-model mice, and whether the sensory ganglia of these mice contain amyloid plaques
and increased numbers of inflammatory cells. Prior studies from our labs have also shown that once the auditory
system has matured, the survival of the neurons in the cochlear nucleus is not dependent on maintained sensory
input. We hypothesize that expression of AD-associated genes will make these neurons become vulnerable to
the loss of synaptic input from the ear, such as routinely occurs with aging. A second set of experiments will test
this hypothesis by determining if the expression of AD-associated mutations causes the neurons of the ventral
cochlear nucleus (VCN) to show increased vulnerability to loss of sensory input. Such an event might result in a
cascade of peripheral and central events leading to increased cognitive and sensory motor decline. The outcome
of these studies may help explain the link between hearing loss and the devilment of Alzheimer’s pathology.

## Key facts

- **NIH application ID:** 10119786
- **Project number:** 3R01DC015790-04S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Edwin W Rubel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,322
- **Award type:** 3
- **Project period:** 2017-07-05 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119786

## Citation

> US National Institutes of Health, RePORTER application 10119786, ROLE OF THE INNATE IMMUNE SYSTEM IN THE SURVIVAL OF AUDITORY NEURONS (3R01DC015790-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119786. Licensed CC0.

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