# ApoE, ABCA1 and endosomal dysregulation in AD

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $717,268

## Abstract

Abstract
Aging and carrying the APOE e4 allele are among the strongest risk factors for developing late-onset Alzheimer’s
disease (AD). Several lines of evidence reveal an increase in endosomal trafficking proteins in the brains of
APOE e4 allele carriers decades before the onset of cognitive decline. However, there is a major gap in our
understanding of the critical mechanisms by which the ApoE4 protein regulates endosomal trafficking. The
activity of the ATP binding cassette 1 (ABCA1) has an important role in the endocytosis of lipid-poor ApoE to
initiate its endosomal recycling. This facilitates lipidation of ApoE and its recycling into the extracellular space.
Loss of ABCA1 activity increases lipid-poor and aggregated ApoE particles. In humans, genetic loss-of-function
mutations in ABCA1 are associated with increased AD risk. We hypothesize that aggregation of lipid-poor ApoE4
is at the root of endosomal trafficking dysregulation, and that activation of ABCA1 to lipidate ApoE decreases its
aggregation and favors its endosomal recycling. To address this hypothesis, we propose the following three
Specific Aims. In Aim 1, we determine the mechanisms of how ApoE and ABCA1 activity regulate endosomal
trafficking in primary astrocytes, neurons and microglia. In Aim 2, we determine the effect of aging, APOE4
genotype and enhancing ABCA1 activity on ApoE aggregation and endosomal trafficking pathways in brains of
ApoE targeted replacement mice, and in existing well-characterized human brain tissues that differ by APOE
genotype and cognitive state. In aim 3, we propose to develop an 18-F CS-6253 PET imaging modality to assess
the effect of APOE e4 and aging on ABCA1 brain activity in vivo. Achieving our aims will provide a detailed
understanding of the effect of APOE4 on endosomal trafficking proteins, demonstrating a novel concept that
activation of ABCA1 can ameliorate the congestion of ApoE4 containing endosomes. The information obtained
is of major significance to understanding early events that predispose to AD pathology and developing
therapeutic strategies focused on enhancing ABCA1 activity.

## Key facts

- **NIH application ID:** 10356167
- **Project number:** 5R01AG067063-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Hussein N Yassine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $717,268
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356167

## Citation

> US National Institutes of Health, RePORTER application 10356167, ApoE, ABCA1 and endosomal dysregulation in AD (5R01AG067063-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10356167. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*