# Role of APOE in endosomal processing of alpha-synuclein

> **NIH NIH RF1** · WASHINGTON UNIVERSITY · 2024 · $99,532

## Abstract

PROJECT SUMMARY/ABSTRACT: Role of APOE in endosomal processing of alpha-
synuclein
Dementia is among the most harmful and costly aspects of Lewy body disease (LBD) which is
comprised of Parkinson disease (PD) and dementia with Lewy bodies (DLB) and shares some
clinical features with Alzheimer’s disease. In particular, dementia and psychosis are often early
and aggressive symptoms in patients with DLB. Pathologically, these illnesses share the feature
of aggregation of misfolded forms of the protein alpha-synuclein (aSyn), termed Lewy bodies,
which spread throughout multiple brain regions during the disease and are toxic to cells. In
addition to Lewy bodies, patients with LBD often have amyloid plaques and neurofibrillary tangles
which are hallmarks of Alzheimer’s disease, and patients with Alzheimer’s disease often have
Lewy bodies in addition to plaques and tangles. The exact mechanism of how aSyn becomes
misfolded and why cognitive decline is accelerated in DLB is unclear. Genetic studies point to a
strong link between increased DLB risk and the APOE4 variant of the gene that encodes
apolipoprotein E, another protein that is also central to Alzheimer’s disease risk. We reported that
mice expressing the APOE4 version of the human APOE gene had accelerated aSyn aggregation
and early death compared to other APOE genotypes. This finding is similar to the effects observed
when human APOE genotypes are expressed in mouse models of Alzheimer’s disease. Our
preliminary data indicate that astrocytes and microglia take up aSyn aggregates and process
them through the endolysosomal pathway, which may serve as a compensatory mechanism to
degrade harmful aSyn aggregates. We propose to examine the cell biological transit of aSyn
aggregates through the endolysosomal pathway in astrocytes and microglia and determine if
there are differences in this trafficking related to APOE genotype. We hypothesize that the APOE4
genotype impairs endolysosomal degradation of aSyn aggregates in both astrocytes and
microglia, and that astrocyte expression of APOE4 in particular drives accelerated aSyn
pathology leading to brain dysfunction and neurodegeneration. We will test whether this effect
occurs mainly due to cell-autonomous changes within astrocytes or microglia themselves,
including related to changes in gene expression in those cells, or whether it is mediated through
secreted apolipoprotein E protein particles that are known to have effects by binding to receptors
on both neurons and glia. The main goal of these experiments is to clarify how APOE genotype
regulates endolysosomal processing of aSyn in glia and how this knowledge can be leveraged to
develop novel treatments for DLB, Alzheimer’s disease, and other related dementias.

## Key facts

- **NIH application ID:** 11082106
- **Project number:** 3RF1AG083753-01S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Albert A Davis
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $99,532
- **Award type:** 3
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11082106

## Citation

> US National Institutes of Health, RePORTER application 11082106, Role of APOE in endosomal processing of alpha-synuclein (3RF1AG083753-01S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11082106. Licensed CC0.

---

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