# Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer's disease

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $809,297

## Abstract

PROJECT SUMMARY
Alzheimer's disease (AD) is the most prevalent senile dementia affecting 4.5 million Americans.
Neuroinflammatory changes are prominent and may significantly contribute to the pathologic process.
Mononuclear phagocytes (brain resident microglia and recruited peripheral monocytes) accumulate around
amyloid plaque in AD brains. However, their exact cellular identity, molecular and functional phenotypes, and
their protective or destructive roles in AD are not well understood. This stems in part from the lack of a specific
molecular signatures for mononuclear phagocytes, cell type-specific antibodies, and analytic tools for in situ
characterization. We identified that a specific microRNA, miR-155, plays a key role in pro-inflammatory
activation of microglia, whereas the TREM2/apolipoprotein E (APOE) axis plays a central role to suppress
homeostatic M0 microglia. This may lead to impaired amyloid-β peptide clearance and acceleration of
neurodegeneration. Thus, the balance between TREM2 and MERTK expression determines the microglial
inflammatory response to apoptotic cells. Restoration of the homeostatic microglia by targeting the specific
MERTK pathway represents a novel immunotherapeutic approach. Our preliminary data demonstrate that
these novel molecular targets (miR-155, APOE, TREM2 and MERTK) are highly connected biological
molecular regulators of microglial phenotypes and thus we will investigate each of these targets to determine
their roles in AD. We hypothesize that danger signals (dead neurons and amyloid-β peptides) alter
functional phenotype of innate immune cells from the homeostatic (M0) to newly discovered
neurodegenerative (MGnD) phenotype. We will address our hypothesis in the following aims:
Aim 1: Targeting Trem2-induced Apoe/miR155 pathway to restore M0-homeostatic microglia in AD
mouse models. We will specifically delete miR-155, Apoe and Trem2 in microglia of AD mouse models.
Aim 2: Restoration of M0-homeostatic microglia via Mertk pathway in humanized APOE4 and AD mice.
We will specifically over-express Mertk in microglia of APOE4 humanized mice and AD mouse models. We will
validate our findings by investigating AD brains from prodromal to advanced stages.
The goal of our investigations is to define new molecular mechanisms of immune and inflammatory processes
that contribute to the development and progression of AD, which in turn will provide a basis for new
approaches for immune based therapy of the disease.

## Key facts

- **NIH application ID:** 9926784
- **Project number:** 5R01AG054672-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Oleg Butovsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $809,297
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926784

## Citation

> US National Institutes of Health, RePORTER application 9926784, Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer's disease (5R01AG054672-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9926784. Licensed CC0.

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