# Deciphering isogenic APOE isoform dependent neurodegenerative response in human glia

> **NIH NIH K01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $123,012

## Abstract

PROJECT SUMMARY
Apolipoprotein E (APOE) is the most significant risk gene for late-onset Alzheimer's disease (AD). APOE ɛ4/ɛ4
homozygosity increases AD risk by >14-fold. Although an association between the APOE ε4 allele and
increased AD risk is well-established, the mechanisms underlying this genetic risk remain elusive. In brain,
microglia and astrocytes induce inflammation and degrade (engulf, digest, store or recycle) lipid-rich cellular
debris that accumulates during aging and neurodegeneration. We hypothesize that APOE ɛ4/ɛ4 genotype has
cell autonomous effects on astrocytes and microglia which affects other cell types. Specifically, we hypothesize
that APOE ε4/ε4 astrocytes and microglia exhibit altered response to lipid-rich debris (myelin fragments),
detectable as changes in global transcription and cellular function. To test this hypothesis we have generated a
unique series of isogenic iPSCs differing solely in APOE isoform using a CRISPR/Cas9 genome-editing tool.
We have established a platform to recapitulate cellular systems of human brain in culture by differentiation of
iPSC-derived astrocytes and microglia that express APOE. We seek to bring together this established patient-
derived isogenic human iPSC model, powerful systems biology, bioinformatic approaches and in vitro
metabolic assays including neuroinflammation, phagocytosis and autophagy to understand the mechanism
underlying APOE risk for AD. This proposed research project sets out to unravel the APOE isoform-dependent
effects in glia and their responses to lipid challenge. In aim 1, we will generate homogenous populations of
astrocytes and microglia and mixed cultures of cortical neurons/glia from isogenic APOE isoforms and APOE
knockout derived from patient iPSCs. We will perform differential gene expression analysis to determine the
downstream effects of APOE genotype in each cell type. In aim 2, we will study APOE isoform-dependent glial
responses to challenge with lipid-rich particles. Following an unbiased transcriptomic approach, we will analyze
which of the disease associated microglia signatures or AD-associated networks are APOE isoform-dependent
upon challenge. In aim 3, we will investigate APOE isoform-dependent effects on the inflammatory response
and phagocytic/autolysosomal clearance of lipid particles. The goal of this project is to identify the
transcriptomic networks and cellular functions governed by APOE genotype in the presence or absence of a
disease relevant environment (myelin debris) to pinpoint the earliest and potentially most treatable
mechanisms involved in AD pathogenesis.

## Key facts

- **NIH application ID:** 10580481
- **Project number:** 7K01AG062683-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Julia TCW
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $123,012
- **Award type:** 7
- **Project period:** 2019-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10580481

## Citation

> US National Institutes of Health, RePORTER application 10580481, Deciphering isogenic APOE isoform dependent neurodegenerative response in human glia (7K01AG062683-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10580481. Licensed CC0.

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