# Investigating the cause of APOE4-associated microglial activation and its resulting neurotoxicity of tauopathy-afflicted neurons

> **NIH NIH K01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $125,402

## Abstract

Project Summary
Possession of the ɛ4 allele of apolipoprotein E (APOE) is a major risk factor for late onset Alzheimer's disease
(AD), although the direct cause remains a source of debate. Recent data has shown that the APOE gene is
upregulated in a novel microglial activation state found in AD and other neurodegenerative diseases termed
disease associated microglia (DAM). Furthermore, APOE4 expression has been shown to induce a neurotoxic
activation of microglia in the presence of various stimuli, including tauopathy-afflicted neurons, although the
mechanism of this activation has yet to be elucidated. In order to discover the role and mechanism of APOE4-
associated microglial activation and its resulting neurotoxicity of tauopathy-afflicted neurons, I have devised an
innovative set of experiments that utilize both cutting-edge technology and novel resources. In Aim 1, single-
cell RNA-sequencing will be performed on microglia purified from a novel mouse line in which human APOE3
and APOE4 mice are crossed with EC-Tau mice, which express a pro-aggregating mutant tau protein primarily
in the entorhinal cortex (EC). In Aim 2, APOE4's effects on microglial activation will be investigated in the
setting of human microglia, using both a newly created isogenic APOE human stem cell line and powerful
bioinformatics analyses. And in Aim 3, a robust in vitro co-culture assay will be utilized in order to both uncover
the mechanism responsible for APOE4-associated microglial activation and the resulting neurotoxicity and to
identify novel therapeutic strategies for inhibiting these events. As both APOE4 and microglial activation
significantly impact AD, discovery of the mechanistic link between these two important players and therapeutic
strategies for modulating APOE4-associated microglial activation would represent a major breakthrough in the
AD field and would greatly advance our goal of preventing or slowing the progression of AD, especially among
APOE4 carriers.

## Key facts

- **NIH application ID:** 10070565
- **Project number:** 5K01AG061264-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Tal Nuriel
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $125,402
- **Award type:** 5
- **Project period:** 2019-02-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070565

## Citation

> US National Institutes of Health, RePORTER application 10070565, Investigating the cause of APOE4-associated microglial activation and its resulting neurotoxicity of tauopathy-afflicted neurons (5K01AG061264-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10070565. Licensed CC0.

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