# Targeting the miR-155 signaling pathway to induce beneficial disease associated microglia subtypes in Alzheimer's Disease

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $46,036

## Abstract

ABSTRACT
Alzheimer’s Disease (AD) is currently the most prevalent neurodegenerative disorder in the world, with the
number of cases expected to triple by 2050. Multiple pathological studies and data from genome wide
association studies (GWAS) have identified microglia and genes specific to microglia as prominent mediators
of AD pathogenesis and progression. Several laboratories have identified a genetic signature of microglia
associated with AD and other neurodegenerative disorders, which have been dubbed “Disease Associated
Microglia” (DAM) or “Microglia Neurodegenerative” (MGnD). It is still unknown whether these DAM/MGnD are
beneficial or detrimental to AD pathology. One popular theory is that blocking DAM/MGnD formation may
result in a beneficial effect in the context of AD, as this has been demonstrated in other animal models of
neurodegeneration. To test this hypothesis in AD we selectively deleted microRNA 155, a microRNA
demonstrated to be a major signaling component for the switch from homeostatic microglia to DAM/MGnD, in
the microglia of mouse models of AD. Surprisingly, our data indicate that miR-155 deletion simultaneously
enhanced expression of several canonical DAM/MGnD genes associated with phagocytosis, and dampened
activity of pathways associated with inflammation and cytokine secretion. This surprising change resulted in an
improvement of amyloid pathology and enhanced cognitive performance. To explain the mechanism for the
acquisition of this signature, we assessed our transcriptomic data for molecular targets of miR-155 that have
significance to AD onset in genetic studies and are upstream regulators of the genes we see differentially
expressed or trending towards differential expression in our miR-155 ablation study data. Two miR-155 targets,
SHIP1 and PU.1, have been identified by AD GWAS studies as top hits for AD onset and are transcriptional
regulators of inflammation and phagocytosis, respectively. Taken together, these data led me to my hypothesis
that the DAM/MGnD signatures are comprised of phagocytic and inflammatory “sub-features” which
can be independently modulated by augmentation of SHIP1 and PU.1. I also hypothesize that the ablation
of miR-155 will result in a similar transcriptional change in human microglia, given the identical conservation of
miR-155 between mice and humans. In Aim 1 of this proposal, I propose to overexpress both SHIP1 and PU.1
in the microglia of AD mouse models using lentiviral vectors. This approach represents an extremely novel
and translatable use of gene therapy technologies to address molecular mechanisms of microglial function. In
Aim 2, I propose to recapitulate the gene signature observed in our microglia specific miR-155 ablation mouse
experiments in human microglia like cells derived from induced pluripotent stem cells to tie the significance of
these findings and this hypothesis to human health and disease.

## Key facts

- **NIH application ID:** 10313271
- **Project number:** 1F31AG071106-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Shawn Strever Herron
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313271

## Citation

> US National Institutes of Health, RePORTER application 10313271, Targeting the miR-155 signaling pathway to induce beneficial disease associated microglia subtypes in Alzheimer's Disease (1F31AG071106-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10313271. Licensed CC0.

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