# Defining microglial and endothelial cell-type specific proteomic alterations of APOE risk in Alzheimer's disease

> **NIH NIH F32** · EMORY UNIVERSITY · 2020 · $65,310

## Abstract

ABSTRACT (PROJECT SUMMARY)
Genome wide association studies (GWAS) of late-onset AD have identified more than 20 genes to be associated
with disease risk, with variation in the apolipoprotein E (APOE) gene being the strongest risk factor. APOE is a
lipoprotein that is known to have functions in cholesterol metabolism, but the mechanisms by which it imparts
AD risk remain poorly understood. APOE has three isoforms ε2 (E2)
, ε3 (E3)
, and ε4 (E4) where individuals with
the ε4 allele are 3-12 times more likely to develop AD and those with ε2 allele have reduced risk of developing
AD. APOE4 affects amyloid beta (Aβ) aggregation, metabolism, and plaque load in both individuals with AD and
mouse models of AD. APOE4 also differentially affects microglial-mediated inflammatory responses in the brain
as well as endothelial-mediated clearance of Aβ in the cerebrovasculature, suggesting that APOE-associated
AD risk may in part be driven by dysfunctional inflammatory and vascular responses to Aβ pathology. At present,
there is a significant gap in our knowledge of what molecular constituents mediate microglial and/or endothelial
disease mechanisms in APOE-linked AD. The consideration of these mechanisms can aid our understanding of
proteins that may work together to affect the disease state or protection, create a framework for the
pathophysiology of the disease, and guide exploration into therapeutic targets.
 The long-term goal of this research is to better understand how APOE genotype effects cellular
phenotypes in brain. To achieve this goal, I will use data-driven proteomic and systems biology approaches to
integrate human and mouse model studies and resolve the impact of APOE genotype on AD risk. Specifically,
the experiments outlined in this proposal will test the central hypothesis that microglial and endothelial
cellular phenotypes in AD are caused by APOE genotype. This hypothesis is supported by my exciting
preliminary data that show APOE genotype impacts global proteomic alterations, microglial and endothelial cell
abundance, and cell-type profiles in human AD brains. These proteomic profiles imply a linkage between the
microglia, endothelia, and APOE-mediated pathophysiologies in AD brain, but since they were obtained from
whole brain tissue, the cell-type specific contributions to the proteomic alterations may be masked. Given this,
we have recently optimized cell isolation and mass-spectrometry (MS)-based techniques to comprehensively
characterize, for the first time, proteomic profiles of brain endothelial cells in parallel with microglia from mouse
brain. I will characterize the proteomic profile of isolated cells from the brains of EFAD transgenic mice to unravel
the impact of APOE genotype on microglial and endothelial molecular phenotypes as well as characterize age-
related changes in these cells. Importantly, these data will provide insight into convergent APOE genotype driven
mechanisms in microglial and endothelial cells in both mice a...

## Key facts

- **NIH application ID:** 10088328
- **Project number:** 5F32AG064862-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Sruti Rayaprolu
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10088328

## Citation

> US National Institutes of Health, RePORTER application 10088328, Defining microglial and endothelial cell-type specific proteomic alterations of APOE risk in Alzheimer's disease (5F32AG064862-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10088328. Licensed CC0.

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