# Mitochondrial-dependent Mechanisms of Apolipoprotein E Gene Expression in the Mammalian Brain

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is a debilitating and common form of dementia, and a leading cause of death in the
United States. Testing of the amyloid hypothesis has overwhelmingly been the focus of research on AD.
According to this hypothesis, pathogenic processing of the Alzheimer’s precursor protein (APP) leads to
accumulation of plaques containing amyloid beta that are a hallmark, and apparent cause, of AD. Despite much
effort, research based on this hypothesis has yet to provide effective therapeutic targets for AD. Thus, alternative
hypotheses invoking causal roles for mitochondria and metabolism of lipids and cholesterol in AD pathogenesis
have also been proposed. While these hypotheses have been tested in relation to the amyloid hypothesis, a
critical mechanistic gap remains in determining whether causal roles for mitochondria and cholesterol/lipid
metabolism in AD pathogenesis may be linked with one another. A role for lipid and cholesterol metabolism in
AD is supported by the fact that an allele of the ApolipoproteinE (ApoE) gene, encoding the primary carrier of
lipids and cholesterol in the brain, is the strongest genetic risk factor for sporadic AD. In contrast, research
examining causal roles for mitochondria in AD has focused on bioenergetics and oxidative stress, although
mitochondria also play known roles in cholesterol and lipid metabolism. Whether mitochondria influence ApoE
expression and/or cholesterol homeostasis in the context of AD remains unexplored and will be the focus of this
proposal. Our preliminary data indicates that reduced expression of the mitochondrial membrane transporter
SLC25A1 increases levels of ApoE and APP. SLC25A1 shuttles the metabolite citrate from mitochondria to the
cytoplasm, where it gets converted to acetyl-CoA that is required for lipid and cholesterol synthesis. The central
hypothesis that will be tested in this proposal is that genetic disruption of the SLC25A1 interactome (SLC25A1
and the network of proteins with which it physically interacts) drives increased ApoE expression and changes in
cholesterol homeostasis, consequently impacting downstream APP production and processing. In Aim 1, the
trainee will determine whether increased ApoE expression is a specific readout indicating dysfunction of
components of the SLC25A1 interactome, or is instead a general response to mitochondrial dysfunction, using
immunoblots, quantitative polymerase chain reaction (RT-qPCR), and lipidomics profiling in primary neurons and
glia. In Aim 2, the trainee will determine whether Slc25a1 gene dosage modulates AD pathology in a mouse
model of AD, using plate-based immunoassays and immunocytochemistry. Completion of these aims will reveal
whether mitochondria contribute to AD pathogenesis through ApoE and/or cholesterol-dependent mechanisms,
as well as whether this influence is specific to a certain hub of mitochondrial proteins involved in lipid/cholesterol
metabolism. These findings will improve our un...

## Key facts

- **NIH application ID:** 9984097
- **Project number:** 1F31AG067623-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Meghan Elyse Wynne
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2021-02-28 → 2024-02-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984097

## Citation

> US National Institutes of Health, RePORTER application 9984097, Mitochondrial-dependent Mechanisms of Apolipoprotein E Gene Expression in the Mammalian Brain (1F31AG067623-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9984097. Licensed CC0.

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