# Epigenetic regulation of sexually divergent neuroinflammation with brain aging and Alzheimer's disease

> **NIH NIH F31** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2021 · $26,624

## Abstract

PROJECT SUMMARY/ABSTRACT
Age and sex are the primary risk factors for developing Alzheimer’s disease (AD), with a higher incidence in
women at all ages from 60-100 years old. Mechanisms underlying the cause of sex differences in AD are not
well understood, preventing the development of sex-specific therapeutic interventions. Chronic, low-grade
inflammation is characteristic of brain aging and neurodegeneration. As the sentinel macrophages of the CNS,
microglia play an important role in sensing and responding to changes in the CNS milieu. Microglia monitor the
CNS for foreign/’non-self’ and endogenous substances, serving both neuroprotective and neurodegenerative
functions. Under normal physiological conditions, microglia retain a relatively quiescent, surveillance phenotype;
however stimulation can polarize microglia to the pro-inflammatory M1 phenotype or anti-inflammatory M2
phenotype. Control of microglial phenotypic switching involves regulation of DNA modifications, principally
methylation and hydroxymethylation of cytosines, which control genome accessibility and gene expression.
Exuberant activation of microglial-specific inflammatory pathways with age in females and sexual divergence in
DNA modifications with age point to an epigenetic role in sex differences in brain aging and neuroinflammation.
However, paired epigenomic and transcriptomic studies have not been conducted in hippocampal microglia with
age between sexes. To address this barrier to progress we developed microglial-specific, tamoxifen-inducible,
transgenic NuTRAP models to allow isolation of nucleic acids (DNA & RNA) from lineage-traced microglia. In
Aim 1, microglial-specific hippocampal changes in mC/hmC with aging will be examined by whole genome
oxidative bisulfite sequencing (WGoxBS). Epigenomic data, and the paired transcriptomic data from the same
animals will be used to determine the role of altered modification patterns in age-related changes in gene
expression, enrichment of differential modifications in regulatory regions of the genome, and to identify genomic
loci for future epigenome editing experiments. Although sexual divergence is documented in some current rodent
models of AD, an acknowledged limitation in the field is that transgenic animals develop AD neuropathology at
a young age, unlike sporadic AD, which occurs late in life. New AD models like amyloid-beta (Aβ) oligomer
infusion allow for examination of AD-related Aβ neuropathology in the context of brain aging and sex effects. In
Aim 2, we combine Aβ-oligomer infusion with our novel NuTRAP model to selectively analyze microglial-specific
epigenomic and transcriptomic changes in the context of Aβ neurotoxicity. Further, immunohistochemistry and
cytokine/chemokine panels are used readouts for gliosis, to assess the effect of aging on Aβ-induced microglial
reactivity between sexes. If successful, these studies will provide insights into sexually divergent microglial
function with aging and Aβ-related neu...

## Key facts

- **NIH application ID:** 10220837
- **Project number:** 5F31AG064861-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Sarah Renee Ocanas
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $26,624
- **Award type:** 5
- **Project period:** 2019-09-16 → 2022-05-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220837

## Citation

> US National Institutes of Health, RePORTER application 10220837, Epigenetic regulation of sexually divergent neuroinflammation with brain aging and Alzheimer's disease (5F31AG064861-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10220837. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*