# Targeting Histone K4 Methylation for Treatment of Alzheimer's Disease and Related Dementia

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $506,436

## Abstract

Summary
Neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal dementia
(FTD) are afflicting a large number of aging people. Mutations in the microtubule-associated
protein tau (MAPT) gene that lead to microtubule disassembly and neuronal degeneration have
been implicated in the pathogenesis of AD and FTD, however effective treatment for these
diseases is still lacking. Emerging evidence suggests that epigenetic dysregulation, which can
induce pathological alteration of gene expression, plays a key role in aging and
neurodegeneration. Using postmortem tissues from AD patients and transgenic mice carrying
mutant human Tau protein associated with FTD and AD, we have found that histone 3
trimethylation at lysine 4 (H3K4me3), which is linked to gene activation, is significantly elevated
in the prefrontal cortex (PFC), a key cognitive region impaired in AD and FTD. More importantly,
we have found that inhibiting H3K4-specific methyltransferases leads to the substantial recovery
of synaptic function in PFC pyramidal neurons, and the significant improvement of memory-
related behaviors in Tau AD model. Based on these intriguing results, we propose to further
reveal the role of H3K4me3 in AD pathophysiology and treatment. Combined molecular,
biochemical, electrophysiological, behavioral, and genomic approaches will be used to identify
aberrant H3K4 methylation in AD human brains and Tau AD model (Aim 1); to examine the
rescue effects of targeting H3K4-specific methyltransferases on synaptic and cognitive deficits
in Tau AD model (Aim 2); to reveal molecular mechanisms underlying the therapeutic effects of
targeting H3K4-specific methyltransferases in Tau AD model. Results gained from this project
will help to identify a novel therapeutic strategy for AD and related neurodegenerative disorders
associated with tauopathies.

## Key facts

- **NIH application ID:** 10173613
- **Project number:** 5R01AG064656-03
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Zhen Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $506,436
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173613

## Citation

> US National Institutes of Health, RePORTER application 10173613, Targeting Histone K4 Methylation for Treatment of Alzheimer's Disease and Related Dementia (5R01AG064656-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10173613. Licensed CC0.

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