# Lipid droplet targeting and function of Apolipoprotein E in astrocytes

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $38,258

## Abstract

ABSTRACT
Apolipoprotein E (ApoE) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Individuals
who possess one or more copies of the APOE4 variant have an increased risk of developing AD, with an
earlier age of onset and more rapid cognitive decline, compared to those with the more common APOE3 allele.
ApoE is expressed primarily in astrocytes, and secreted on lipoprotein particles to provide cholesterol and
unsaturated phospholipids for membrane expansion and synapse formation in neurons. However, little is
known regarding the basic molecular mechanisms behind ApoE function in astrocytes, and how the E4 variant
promotes disease. I have discovered that ApoE can traffic either to the secretory pathway or to cytoplasmic
lipid droplets in astrocytes. My central hypothesis is that ApoE can be stimulated to target lipid droplets in the
cytoplasm rather than being secreted, and that it is involved in promoting the storage of neutral lipids within
lipid droplets. I also hypothesize that the lipid droplet function of ApoE is altered in the disease-associated E4
and E2 variants. To test this hypothesis, I will perform structure-function studies to determine which regions of
the protein are necessary for ApoE to target the cytoplasmic compartment and localize to lipid droplets. I will
examine how ApoE trafficking is controlled by neuronal signals by performing astrocyte-neuron coculture
assays. To determine the function of ApoE targeted to lipid droplets, I will use shRNA to knockdown ApoE and
observe the effect on the distribution of neutral lipids in the cell. I will then determine whether ApoE regulates
lipid droplet biogenesis, growth, or turnover via fluorescent lipid pulse-chase assays coupled with time-lapse
microscopy and automated image analysis. I will compare the trafficking and function of the different variants
of ApoE to test whether the lipid droplet function is altered in E2 and E4. This project will uncover how ApoE
variants regulate lipid droplet metabolism in astrocytes.

## Key facts

- **NIH application ID:** 10456182
- **Project number:** 5F31AG069419-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ian Andrew Windham
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,258
- **Award type:** 5
- **Project period:** 2020-09-09 → 2023-09-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456182

## Citation

> US National Institutes of Health, RePORTER application 10456182, Lipid droplet targeting and function of Apolipoprotein E in astrocytes (5F31AG069419-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10456182. Licensed CC0.

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