# An interneuronal signaling network governs the fate of retinal ganglion cells after optic nerve injury

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $442,500

## Abstract

Alzheimer's disease (AD) is a common devastating neurodegenerative disease. As with other chronic
neurodegenerative diseases, the pathogenesis remains unknown, even though gene mutations causing
familial AD were discovered over 20 years ago. The neuropathology of AD is characterized by extracellular
amyloid plaques, comprised primarily of fibrillar Abeta 1-40 and Abeta 1-42 proteins derived from amyloid
precursor protein (APP) and intracellular neurofibrillary tangles comprised primarily of tau protein. Abeta
protein deposition is promoted by interaction with zinc. Abundant evidence supports the hypothesis that
amyloid plaques themselves are not toxic but rather the toxicity is primarily due to the soluble oligomeric Abeta
1-42 fragment of APP (oAβ). Several of the mutations that cause AD affect the processing of APP to increase
the production of oAβ, consistent with the amyloid hypothesis. The eye is part of the central nervous system
(CNS), and an extension of the amyloid hypothesis has developed over the last 15 years with the recognition
that the retina is affected by the deposition of Abeta in AD, and that Abeta may play a role in retinal diseases
involving degeneration of retinal neurons such as glaucoma and age-related macular degeneration. Optic
nerve injury (ONI) is another important retinal disorder, and the consequences of transection of axons in the
optic nerve is death of retinal ganglion cells and failure of axon regeneration. There has been little or no study
of the role of Abeta production and deposition in the neurodegeneration and failure of regeneration following
ONI, or how ONI might affect APP processing. In preliminary experiments, using an antibody against Abeta
proteins, we have found Abeta aggregates at the site of injury to the optic nerve forming weeks after injury in
normal animals but not in animals with a knockout of the zinc transporter ZnT3. We hypothesize that APP
processing is highly influenced in the retina by ONI and, that APP processing may play important roles in the
neuronal loss and regenerative failure following ONI. To test this hypothesis, we propose the following aims:
Aim 1. Characterize APP expression and Abeta deposition in the normal mouse retina and following ONI.
Aim 2. Assess the effects of altering zinc homeostasis and tetanus toxin on the processing of APP after ONI.
Aim 3. Assess the effect of blocking Abeta production on neuronal survival and regeneration failure after ONI.
RELEVANCE TO ALZHEIMER'S DISEASE: Our understanding of the processing of APP is incomplete.
The cause of abnormal production of Abeta in sporadic AD is unknown as is the basis for the toxicity of oAβ to
neurons. APP processing, Abeta production, and Abeta aggregation are influenced by oxidative stress, zinc
and copper homeostasis, neuronal activity, axonal transport, and growth state of axons all of which are
important in the pathophysiology of ONI. The ONI model offers a uniquely accessible in vivo model of the
CNS for th...

## Key facts

- **NIH application ID:** 10123331
- **Project number:** 3R01EY027881-03S1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** LARRY Ira BENOWITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,500
- **Award type:** 3
- **Project period:** 2018-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123331

## Citation

> US National Institutes of Health, RePORTER application 10123331, An interneuronal signaling network governs the fate of retinal ganglion cells after optic nerve injury (3R01EY027881-03S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10123331. Licensed CC0.

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