# Defining the Function of APOE in Autophagy and Neurodegeneration

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $51,036

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's Disease (AD) is the most common cause of dementia, affecting 1 in 10 over the age of 65 in the
United States. AD is debilitating and fatal, and no effective treatments are available. Dysregulation of autophagy,
the process of transporting cellular waste to the endo-lysosomal system for degradation, has been proposed as
a mechanism involved in AD and many other neurodegenerative diseases. Autophagy can be down-regulated
by both normal aging and mutation of proteins with autophagic functions. The greatest genetic risk factor for late
onset AD is APOE. I hypothesize that APOE functions as a selective autophagic receptor protein, and that the
disease-associated APOE4 isoform dysregulates autophagy, contributing to disease. APOE4 impairs autophagy
in mouse astrocytes, reduces autophagy gene transcription in a human glioblastoma cell line, and results in
dramatic endosomal enlargement in the early stages of AD. APOE transports the majority of the brain's lipids,
and lipid accumulation is one of the pathological hallmarks of AD, suggesting that lipid clearance may be
impaired. It has not yet been tested whether APOE may impact autophagic function directly as part of the
autophagy machinery. APOE has several properties of established autophagy receptors, including localization
in acidic compartments and oligomerization. It was recently shown that APOE interacts with mammalian Atg8s
during autophagy, a key characteristic of autophagy receptors. Protein sequence alignment data suggests that
APOE may have some similarity to the yeast autophagy protein Atg39, a recently discovered receptor for the
autophagy of lipids and the endoplasmic reticulum. The Aims of this proposal are as follows. Aim 1: Assess
APOE interactions with the autophagy machinery. I will investigate APOE's function as an autophagic receptor
protein in part by defining its interactions with autophagy machinery proteins. Aim 2: Examine accumulation of
autophagic substrates upon APOE knockdown. Here, I will determine whether APOE is required for selective
autophagy of lipids and endoplasmic reticulum. Aim 3: Assess impact of APOE isoforms on autophagic
degradation. For this aim, I will assess whether the disease-causing APOE4 allele can impact autophagic
turnover of APOE, autophagosome formation, and accumulation of autophagic substrates. These aims will begin
to determine whether APOE has a novel function as an autophagic cargo receptor. Investigating the functions of
APOE in autophagy, and whether the APOE4 isoform impairs or enhances those functions, may offer insight
into the types of autophagy modifying therapies that could benefit millions of patients with AD.

## Key facts

- **NIH application ID:** 10173594
- **Project number:** 5F30AG060704-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Gianna Fote
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-05-28 → 2022-05-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173594

## Citation

> US National Institutes of Health, RePORTER application 10173594, Defining the Function of APOE in Autophagy and Neurodegeneration (5F30AG060704-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10173594. Licensed CC0.

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