# Epigenetic Mechanism Linking Diabetes and Cognitive Dysfunction

> **NIH VA I01** · JAMES J PETERS VA  MEDICAL CENTER · 2020 · —

## Abstract

SUMMARY
The overall goal of the proposed studies is to test the hypothesis that type 2 diabetes (T2D)-induced epigenetic
changes in the brain may contribute to cognitive decline by altering the expression of mitochondrial and
synaptic genes, resulting in cellular energy metabolism dysregulation and neuronal and dendritic spine
structure/activity impairments, ultimately leading to cognitive dysfunction. It is known that diabetes is a risk
factor for dementia. However, the underlying mechanisms linking T2D and cognitive decline are largely
unknown. Emerging evidence has demonstrated that T2D-associated chromatin modifications pertinent to
epigenetic mechanisms play an important role in the pathogenesis of diabetes. We found significant
upregulation in the expression of select chromatin modification enzymes, histone deacetylases (HDACs) class
IIa in the brains of T2D subjects compared to non-T2D control subjects, and found that these changes coincide
with altered expression of proteins involved in synaptic function. Using an experimental mouse model of T2D,
we found similar epigenetic changes in the brains, and the mice also exhibited impairments in energy
metabolism, synaptic plasticity, and spatial memory function. Treatment with an HDAC class IIa specific
inhibitor can effectively restore synaptic plasticity in hippocampal slices isolated from these T2D mice, and
improves energy metabolism in vitro, indicating that HDAC class IIa might play an important role in T2D-
induced energy metabolism dysregulation and synaptic impairments in the brain. Based on this evidence, we
propose to systematically and mechanistically investigate, both in vitro using primary neurons and in vivo using
a mouse model of diabetes, how diabetes-mediated epigenetic changes may affect molecular and cellular
pathways that lead to dysregulation of energy metabolism, impairments in synaptic plasticity, and cognitive
dysfunction. Our proposed studies will clarify the role of HDAC IIa in diabetes-mediated cognitive impairment
and provide novel therapeutic targets for prevention or treatment of cognitive dysfunction in the context of T2D.

## Key facts

- **NIH application ID:** 9932289
- **Project number:** 5I01BX003523-04
- **Recipient organization:** JAMES J PETERS VA  MEDICAL CENTER
- **Principal Investigator:** Jun Wang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932289

## Citation

> US National Institutes of Health, RePORTER application 9932289, Epigenetic Mechanism Linking Diabetes and Cognitive Dysfunction (5I01BX003523-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9932289. Licensed CC0.

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