# APOE e4 negative regulation of microglia-astrocytes crosstalk in Alzheimer's disease

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $429,168

## Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Microglia play an essential role in
supporting normal CNS functions, but in disease may contribute to neurodegeneration. We identified
homeostatic (M0) and neurodegenerative (MGnD) microglia, also referred to as disease associated microglia
(DAM), that are regulated by the reciprocal suppression of TGFb and induction of APOE signaling in different
neurodegenerative mouse models including AD. However, the role of these two major phenotypes and how they
affect disease progression remains a major question. Importantly, targeting microglial APOE signaling restored
the homeostatic signature of microglia associated with neuroprotection in acute and chronic models of
neurodegeneration. APOE signaling suppressed PU.1 and TGFβ signaling in a cell-autonomous manner. Human
APOE has three variants: ε2, ε3, and ε4. APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer’s
disease (LOAD). Our preliminary data show: 1) Increased expression of PU.1 in microglia from humanized APOE
ε4 mice; 2) Expression of APOE ε4 in microglia impaired microglial response to induce a MGnD phenotype and
3) Deletion of microglial APOE ε4 restored MGnD phenotype in APP/PS1 mice associated with astrocytes
recruitment towards Ab-plaques and reduction in neuritic plaques. These data indicate that APOE ε4 signaling
is a crucial regulatory pathway in microglia in APP/PS1 mice. Based on these findings, we hypothesize that in
APOE ε4 carriers, APOE ε4 ‘locks’ microglia in their homeostatic state leading to impaired phagocytic
functions and dysregulated microglia-astrocyte crosstalk, which could have fundamental consequences
for AD development. We will address our hypothesis in the following aims:
Aim 1: Determine the role of APOE ε4 on transcriptional regulation of microglia and their crosstalk with
astrocytes in AD and non-demented subjects carrying different APOE alleles. We will determine whether
human APOE ε4 affects transcriptional signatures of cellular response, interactive pathways, and functional
regulation, focusing on microglia and astrocytes.
Aim 2: Validate the spatial differences in APOE ε4 microglia and astrocytes at single-cell resolution. We
will validate the differences in microglia and astrocytic gene expression in brain, using immunohistochemistry of
specific markers and multiplexed error-robust fluorescence in situ hybridization (MERFISH).
IN SUMMARY, this study aims to validate whether APOE ε4 impairs transcriptional, spatial, and functional
regulation of MGnD-microglia and their crosstalk with astrocytes in AD brain.

## Key facts

- **NIH application ID:** 10429190
- **Project number:** 1R21AG076982-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Oleg Butovsky
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,168
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10429190

## Citation

> US National Institutes of Health, RePORTER application 10429190, APOE e4 negative regulation of microglia-astrocytes crosstalk in Alzheimer's disease (1R21AG076982-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10429190. Licensed CC0.

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