# Epigenetic roles of DNA adenine methylation in Alzheimer's Disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $395,513

## Abstract

Alzheimer's disease (AD) is an irreversible, progressive brain disorder featuring gradual decline in memory,
language and other areas of cognition. AD is the most common cause of dementia among the elderly worldwide,
but no effective treatments are available. Aging has been demonstrated to be the primary risk factor for AD
onset. Mounting evidence at the molecular level suggests epigenetic regulation, such as chemical modifications
on DNA molecules that modulate special and temporal gene expression, plays fundamental roles in aging
progression and AD pathogenesis. Methylation on the DNA adenine, N6-methyladenine (6mA) that enriched in
the bacteria genome, was recently found in higher eukaryotic genomes, including mammals. 6mA is dynamically
regulated during embryonic development and could play epigenetic roles in regulating gene and transposon
expression. However, the molecular functions of 6mA, particularly in the brains, remain largely unexplored. Our
preliminary study highlights that 6mA, and its molecular machinery, is required for proper neurodevelopment in
Drosophila brains. Consistently, we found a dynamic regulation of 6mA during postnatal mouse brain and human
embryoid body development. Environmental chronic stress induces dynamic alteration of 6mA in mouse brains,
in the loci highly correlated with depression. Importantly, we found global alterations of 6mA and its putative
molecular machinery in the brains of human AD patient and an AD mouse model. Our data strongly support 6mA
serve as a causal mechanism to contribute to AD pathogenesis. However, there is little research precisely
examining the brain region-specific and neuronal cell type-specific 6mA dynamics during aging progression and
AD-associated alterations. Furthermore, the lack of knowledge regarding the 6mA methyltransferases (“writers”)
and its binding proteins (“readers”) in the mammalian genome limits our understanding of 6mA-dependent
epigenetic regulation in normal and diseased brains. Furthermore, the epigenetic roles of 6mA in
excitation/inhibition balance of neural circuitries whose perturbation linked to AD pathogenesis remain
completely unexplored. Based on these data, we hypothesize that 6mA and its molecular machinery play crucial
roles in aging and their dysregulation contribute to AD pathogenesis. We will first delineate 6mA profiling in
various brain regions and excitatory/inhibitory neuronal subtypes associated with aging and their dysregulation
in AD (Aim 1). We will then define the functions of N6amt1 as a 6mA methyltransferase and determine their roles
in aging and AD in excitatory and inhibitory neurons (Aim 2). Our data suggest 6mA could potentially antagonize
or recruit hypoxia-induced factor-1 (Hif1) and Drosophila Polycomb (Pc), respectively. Based on these results,
we will determine the roles of Hif1 and mammalian Polycomb proteins in aging and AD at the neuronal levels as
well (Aim 3). Findings of this study will provide a novel mechanistic insight ...

## Key facts

- **NIH application ID:** 9984241
- **Project number:** 5R01AG062577-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Bing Yao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,513
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984241

## Citation

> US National Institutes of Health, RePORTER application 9984241, Epigenetic roles of DNA adenine methylation in Alzheimer's Disease (5R01AG062577-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9984241. Licensed CC0.

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