# Tet-mediated Epigenetic Regulation in Alzheimer's Disease

> **NIH NIH F31** · EMORY UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY
AD is caused by the progressive decay of neuronal connections ultimately leading to neuronal death. Loss of
homeostatic neuronal function leads to severe cognitive decline in patients, inhibiting their ability to function in
day-to-day life without extensive help from healthcare providers. The causes of AD are largely unknown;
however, our current understanding recognizes that genetic, epigenetic, and environmental factors play a role
in the disease. As epigenetic modifications are influenced by environmental factors and influence gene
expression, they serve as a mediator between an individual’s genetic composition and phenotypic
characteristics. Thus, epigenetic modifications hold promise to explain a significant portion of the missing
heritability of AD, and several links between the epigenome, TET2, and AD have already been uncovered. Here
we aim to identify novel TET2 variants associated with AD, and examine both how these variants and a reduction
in abundance of TET2 lead to dysregulation of the methylome and how these alterations contribute to AD
pathogenesis. Through examining the influence of TET on AD, we will advance our understanding on the role
DNA hydroxymethylation plays in the brain regions most adversely affected by AD and how these changes
influence gene expression, AD pathology, and learning and memory. Previously, our lab shed light on the role
5mC and 5hmC modifications play in neurodevelopment and several neurological disorders. Additionally, our lab
identified differentially hydroxymethylated sites enriched in AD patients relative to controls and characterized the
global 5hmC prevalence in an AD mouse model. More recently, we produced preliminary data to show
enrichment of TET2 loss of function variants in individuals with early onset Alzheimer’s disease (~1.4% cases
versus 0.12% controls). Building upon these previous findings, we will manipulate 5hmC modification profiles in
an Alzheimer’s disease mouse model to investigate how dysregulation of TET enzymes contributes to AD
pathogenesis. In conjunction with characterization of the methylome (measured via 5hmC Capture), we will
analyze gene expression (measured via RNA-seq) and AD progression (measured via behavioral assays, and
immunohistochemistry of Aβ plaques and neuronal populations) in wildtype and 5XFAD, a beta-amyloid plaque
AD mouse model. These assays will be performed on tissues collected from the cortex and hippocampus. Our
long-term goal is to identify novel AD associated TET2 mutations and how mutations in TET enzymes disrupt
the balance of 5hmC signatures. Our findings may provide greater insight on genomic variants that contribute to
AD risk, specific 5hmC profiles with the potential to be used as biomarkers for AD as well as variations in 5hmC
profiles which confer AD pathogenicity or protection.

## Key facts

- **NIH application ID:** 10400030
- **Project number:** 5F31AG072907-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Matthew Armstrong
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400030

## Citation

> US National Institutes of Health, RePORTER application 10400030, Tet-mediated Epigenetic Regulation in Alzheimer's Disease (5F31AG072907-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10400030. Licensed CC0.

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