# Age-dependent activation of microglia inflammatory state and its epigenetic modulation

> **NIH NIH RF1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $2,994,272

## Abstract

Project Summary
This proposal addresses the epigenetic mechanisms of systemic microglia activation during ageing and its
contribution to neurodegenerative diseases. Ageing in mice and human is associated with the increased
expression of pro-inflammatory genes in microglia and microglia pro-inflammatory activation is considered one
of the causes of age-associated neurodegenerative diseases including Alzheimer disease. The age-associated
increase in microglia-driven inflammation is linked to an aberrantly heightened response of microglia to
different inflammatory stimuli. The enhanced state of microglia activation during ageing resembles the state of
trained immunity where initial immune cell exposure to various pro-inflammatory causes quantitate and
qualitative long-lasting changes in cell responses to environmental triggers. We hypothesize that increased
pro-inflammatory activity of microglia reflects the history of microglia exposure to inflammatory signals during
animal or human life. We argue that infectious diseases, many of which can occur early in life, and the
accompanied systemic inflammation exposes microglia to periphery-derived pro-inflammatory signals.
Exposure to pro-inflammatory triggers can leave an epigenetic imprint that drives heightened inflammatory
gene expression in ageing microglia. To test this hypothesis, we will induce transient systemic inflammation in
mice followed by the analysis of gene expression at differed ages. The long-lasting changes in gene
expression that follow innate immune cell activation has been previously linked to the activation of latent
enhancers. We propose to determine the activation state of microglia enhancers after initial activation followed
by the lifelong monitoring of the enhancer activity. We demonstrated that treatment of microglia with
pharmacological inhibitors of BET proteins, that play a prominent role in enhancer activity, leads to the potent
suppression of microglia activation in vitro and in vivo. Most notably, treatment with BET inhibitors has a major
therapeutic impact on mice that suffer from AD. We will address the specific contribution of individual BET
proteins to pro-inflammatory gene expression and enhancer activation during ageing and in
neurodegeneration. This information is highly relevant for our understanding of the epigenetic mechanisms that
govern the systemic age-associated microglial inflammatory state and may lead to the development of novel
approaches for the treatment of neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10032850
- **Project number:** 1RF1AG068558-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Anne Schaefer
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,994,272
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10032850

## Citation

> US National Institutes of Health, RePORTER application 10032850, Age-dependent activation of microglia inflammatory state and its epigenetic modulation (1RF1AG068558-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10032850. Licensed CC0.

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