# Exploring the role of GADD45A in Alzheimer's disease

> **NIH NIH R21** · EMORY UNIVERSITY · 2022 · $416,071

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is a severe form of dementia that affects over 5 million Americans, making it one of
the most common neurodegenerative disorders. Patients with AD exhibit a severe form of progressive memory
loss that cannot be prevented with current pharmacological interventions, and are at increased risk of developing
comorbid neurological disorders such as epilepsy. The lack of efficacious treatments and the intensive care
required for late-stage AD patients also places a significant economic burden on families and the American
healthcare system: an estimated ~$200 billion annually. Recent studies have demonstrated a link between
epigenetic modifications and AD. One epigenetic modification of particular relevance is 5-hydroxymethylcytosine
(5hmC) which is highly enriched in neurons and is dynamically regulated during neurodevelopment. Alterations
in 5hmC have been observed in the brains of patients with AD and in mouse AD models, raising the possibility
that aberrant DNA 5hmC might contribute to AD pathogenesis. GADD45A mediates the establishment of 5hmC
in cells and also possesses RNA binding activity. Interestingly, Gadd45a-/- null mice exhibit decreased
hippocampal long-term potentiation (LTP) and impaired long-term memory and reversal learning, whereas
overexpression of Gadd45a in pyramidal excitatory neurons of wild-type mice enhances LTP and memory
consolidation. In addition, our preliminary data and publicly available RNA-seq data sets indicate that GADD45A
is downregulated in neurons isolated from AD patients. Gadd45a expression and 5hmC levels are also reduced
in several mouse models of AD (including the 3xTG AD model to be used in this proposal). Based on these
observations, we hypothesize that GADD45A plays an important role in neuronal function and cognition
through epigenetic regulation of 5hmC levels and subsequent modulation of gene expression in
neurons. We will test this hypothesis in Aim 1 by comparing 5hmC levels and distribution between Gadd45a-/-
null mutants and WT littermates. We will also perform RNA-seq and ATAC-seq on these mice to functionally
relate observed changes in 5hmC with specific alterations in gene expression and chromatin accessibility. Given
that overexpression of Gadd45a enhances LTP and memory consolidation, we hypothesize that
upregulation of GADD45A will be therapeutic in AD. Therefore, in Aim 2, we will examine whether
overexpression of Gadd45a in the 3xTG mouse model of AD can ameliorate deficits in synaptic activity, improve
learning and memory, and reduce spontaneous epileptiform discharges. These phenotypes were selected
because they represent important pathological features of AD and are mechanistically related since cognitive
decline in the AD brain is believed to be accelerated by neuronal hyperexcitability.

## Key facts

- **NIH application ID:** 10373344
- **Project number:** 1R21AG072767-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Andrew P Escayg
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $416,071
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373344

## Citation

> US National Institutes of Health, RePORTER application 10373344, Exploring the role of GADD45A in Alzheimer's disease (1R21AG072767-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10373344. Licensed CC0.

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