# Mitochondrial Protection in Glaucomatous Optic Neuropathy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $394,991

## Abstract

Alzheimer’s disease (AD) is one of the most prevalent and complex neurodegenerative diseases worldwide.
Accumulating evidence indicates that AD is potentially linked to alterations of mitochondrial dynamics and
function, indicating that mitochondrial dysfunction is a potential therapeutic target for AD intervention and
treatment. However, no current therapies prevent the disease. A-kinase anchoring protein 1 (AKAP1) is an outer
mitochondrial membrane-targeted AKAP that regulates mitochondrial dynamics and contributes to mitochondrial
network, bioenergetics and calcium homeostasis. Recently, our group has discovered that 1) loss of AKAP1
triggers mitochondrial fission dynamin-related protein 1 (DRP1)-mediated mitochondrial fragmentation,
deregulates oxidative phosphorylation, and induces metabolic and oxidative stress, 2) neuronal AKAP1 has
potent neuroprotective properties by inhibiting DRP1, enhancing mitochondrial activity, and blocking apoptotic
cell death. These results suggest the possibility that modulation of AKAP1 has therapeutic potential in
mitochondrial dysfunction and neurodegeneration. Our preliminary data showed that 1) amyloid precursor protein
(APP)/presnilin 1 (PS1) mutation induces a significant loss of AKAP1 and reduction of DRP S637
phosphorylation, 2) APP/PS1 mutation induces a significant reduction of optic atrophy type 1, 3) APP/PS1
mutation induces a significant reduction of peroxisome proliferator-activated receptor-gamma coactivator 1α and
mitochondrial transcription factor A expression, and 4) APP/PS1 mutation induces an increase of BAX and BCL-
xL expression in the retina of young APP/PS1 mice. Based on these findings, our proposal has two specific aims.
In Aim 1, we will determine whether AKAP1 deficiency contributes to the impairment of mitochondrial
bioenergetics and structure in AD retinal ganglion cells (RGCs). We will investigate structural and functional
changes of mitochondria, mitophagosome formation in AD mice and test the effect of AKAP1 deficiency on
mitochondrial dysfunction in RGCs and hippocampal neurons using AKAP1-/- APP/PS1 mice. In Aim 2, we will
determine the protective effect of AKAP1 amplification on AD RGCs. We will investigate if AKAP1 amplification
preserves mitochondrial structure and function and prevents dendritic arbor alteration and synaptic losses in
APP/PS1 RGCs and hippocampal neurons. We anticipate that these studies will enhance our understanding of
how AKAP1 regulates mitochondrial networks and functions in the early stage of AD pathogenesis. Also, this
proposal will probe AKAP1 amplification as a strategy to induce neuroprotection in both the retina and brain
against AD and related dementias.

## Key facts

- **NIH application ID:** 10711446
- **Project number:** 3R01EY031697-03S2
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** WONKYU JU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $394,991
- **Award type:** 3
- **Project period:** 2020-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10711446

## Citation

> US National Institutes of Health, RePORTER application 10711446, Mitochondrial Protection in Glaucomatous Optic Neuropathy (3R01EY031697-03S2). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10711446. Licensed CC0.

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