# A Novel Epigenetic Mechanism for Alzheimer's Disease

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $398,750

## Abstract

Summary
The major goal of this project is to find out novel treatment strategies for Alzheimer’s disease (AD), a
devastating neurodegenerative disorder afflicting a large number of people. A combination of genetic risk
factors and environmental factors, which leads to deregulation of vulnerability genes, may be most relevant to
the pathogenesis of AD. Eepigenetic mechanisms are suggested to be central to the manifestation of
pathological gene alteration and might act as a bottleneck to mediate gene-environment interactions relevant
to disease progression. Using the transgenic mice carrying 5 familial AD (5xFAD) mutations on human amyloid
precursor protein and presenilin 1, we have found that glutamatergic transmission is significantly diminished in
cortical pyramidal neurons of 5xFAD mice (5-6 months), which is accompanied by the loss of AMPA and
NMDA receptor transcription and expression. Moreover, the repressive histone methylation, which is linked to
gene silencing, is significantly elevated in 5xFAD mice. We hypothesize that abnormal epigenetic regulation of
glutamate receptor transcription resulting from aberrant histone methylation underlies the synaptic and
cognitive deficits in AD, and targeting the histone methyltransferases provides a novel strategy for AD
treatment. To test this hypothesis, three specific aims will be addressed. Aim 1. To identify key epigenetic
mechanisms causing the synaptic and cognitive deficits in AD mouse models. We will examine the alteration of
histone methyltransferases (HMTs) and histone methylation at the promoter regions of glutamate receptors in
AD mouse models with amyloid plaques or neurofibrillary tangles. Aim 2. To investigate the rescue of synaptic
and cognitive deficits by targeting key epigenetic molecules in AD mouse models. We will examine whether
inhibiting the euchromatic histone methyltransferases, EHMT1 and EHMT2, which repress transcription, could
lead to the recovery of synaptic function and the amelioration of cognitive impairment in AD mice. Aim 3. To
examine the molecular alteration and treatment strategy in human stem cell-derived neurons from AD patients.
To find out whether the epigenetic treatment strategy found in AD mouse models might also work in AD
patients, we will take advantage of the innovative stem-cell technology to examine human neurons
differentiated from induced pluripotent stem cells (iPSC) derived from skin fibroblasts. We will examine the
alterations of glutamate receptor transcription and function, as well as histone methylation, in human neurons
from AD patients, and the capability of EHMT1/2 inhibitors to reverse synaptic deficits. Results gained from this
project will help to define disease-specific epigenetic signatures and identify corresponding therapeutic
strategies for AD.

## Key facts

- **NIH application ID:** 10137863
- **Project number:** 5R01AG056060-05
- **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:** $398,750
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-10-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137863

## Citation

> US National Institutes of Health, RePORTER application 10137863, A Novel Epigenetic Mechanism for Alzheimer's Disease (5R01AG056060-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137863. Licensed CC0.

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