# Assessing the role of APOE in glial lipid droplet metabolism and function

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $67,904

## Abstract

ABSTRACT
Alzheimer’s disease (AD) is one of the predominant causes of disability and dependency among older
people, and the sixth leading cause of death in the United States. Late-onset AD is the most common form,
with more than 99% of AD cases occurring after age 65. The strongest genetic risk factor for developing
late-onset AD is carrying the APOE4 allele. Apolipoprotein E (APOE) is primarily expressed by glial cells in
the brain and is the major protein component of lipoprotein particles secreted by astrocytes and microglia.
Lipoprotein particles provide a bidirectional mechanism of lipid transport between glia and neurons. Many
recent studies suggest that a disequilibrium in nervous system lipids is associated with increased risk of
developing AD. However, the mechanisms by which APOE4 affects cellular lipid homeostasis are
incompletely understood. We recently discovered that in glia, APOE can traffic to cytoplasmic lipid droplets
(LDs) rather than undergoing secretion on lipoprotein particles. We hypothesize that APOE plays previously
unrecognized roles in cellular lipid metabolism by acting directly on LDs in astrocytes and microglia.
Astrocytes play important roles in metabolizing peroxidated lipids, while microglia are the primary innate
immune effector cells of the central nervous system. In Aim 1, we will test the effect of modulating APOE in
astrocytes on cellular lipid composition, metabolism, and lipid peroxidation. In Aim 2, we will test the effect
of modulating APOE in microglia on cellular lipid composition, metabolism, and inflammation. In Aim 3, we
will fill a key knowledge gap by developing a community resource visualizing and quantifying LDs in various
brain regions and cell types in mice of different genotypes and ages. Together, these studies will lead to
new insights about the cellular and molecular mechanism by which expression of APOE4 leads to increased
risk of late-onset AD. This work could also lead to the identification of novel drug targets for preventing and
treating AD.

## Key facts

- **NIH application ID:** 11056932
- **Project number:** 3R01AG081421-02S1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Sarah Cohen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $67,904
- **Award type:** 3
- **Project period:** 2023-05-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11056932

## Citation

> US National Institutes of Health, RePORTER application 11056932, Assessing the role of APOE in glial lipid droplet metabolism and function (3R01AG081421-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11056932. Licensed CC0.

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