# Reprogramming Microglial Epigenetic Pathways to Promote Cognitive Recovery after Brain Trauma.

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $450,998

## Abstract

Project Summary: Traumatic brain injury (TBI) triggers delayed molecular secondary injury cascades, including
chronic neuroinflammation, that contribute to progressive tissue loss and neurological deficits, including
dementia. We have shown that microglia are chronically activated for months-to-years following experimental
TBI in mice, contributing to progressive neurodegeneration associated with cognitive decline. Microglia also
undergo changes in their activation profile that may contribute to cognitive decline during neurodegenerative
diseases, including Alzheimer’s disease (AD) and dementias of non-AD type. An important component of these
pathological states is the maladaptive transformation of microglia from a neurorestorative/neuroprotective
phenotype to a persistent, dysfunctional neurotoxic activation state. Our new studies show that microglia isolated
from chronically injured brain display deficits in phagocytosis in parallel with elevations of pro-inflammatory
cytokines and senescence markers, indicative of a chronic dysfunctional/neurotoxic activation state.
Furthermore, we identify specific histone acetylation (H3K9ac) and methylation (H3K27me3) changes in
neurotoxic microglia, which implicate intrinsic epigenetic mechanisms as drivers of this chronic phenotype.
Importantly, new pilot data show that global removal of microglia from the chronically injured brain by short-term
administration of a CSF1R inhibitor (PLX5622) starting at 1-month post-injury results in the repopulation of the
injured brain with microglia with an anti-inflammatory phenotype. This process of resetting microglial activation
after TBI dampens the chronic neuroinflammatory environment and improves long-term motor and cognitive
function recovery. Thus, our data indicates that erasing posttraumatic immunological memory, by removing
microglia epigenetically programmed toward a neurotoxic activation state, promotes neuroprotective microglial
activation responses and improves long-term neurological recovery. Therefore, we hypothesize that moderate-
severe TBI induces specific epigenetic mechanisms in microglia that promote a chronic neurotoxic activation
state, causing progressive neurodegeneration and cognitive deficits. Moreover, we predict that strategies that
eliminate this microglial phenotype and/or targeted inhibition of pro-inflammatory epigenetic mechanisms, even
at highly delayed time points after TBI, can substantially improve long-term cognitive recovery. Here, we will use
neurobehavioral, immunological, and molecular approaches to test our novel hypotheses as outlined in following
specific aims: 1) To elucidate TBI-induced intrinsic epigenetic changes that lead to chronic microglial dysfunction,
with a shift toward a pro-inflammatory, neurotoxic phenotype. 2) To demonstrate that microglia that repopulate
the injured brain following delayed administration of CSF1R inhibitor are reprogramed toward a neurorestorative
and neuroprotective phenotype that improv...

## Key facts

- **NIH application ID:** 10130644
- **Project number:** 5R01NS110756-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ALAN Ira FADEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,998
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130644

## Citation

> US National Institutes of Health, RePORTER application 10130644, Reprogramming Microglial Epigenetic Pathways to Promote Cognitive Recovery after Brain Trauma. (5R01NS110756-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130644. Licensed CC0.

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