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Disruption of histone acetylation homeostasis triggers cognitive dysfunction in experimental diabetes

Aanchal Aggarwal1, Binduma Yadav2, Nishtha Sharma1

  • 1National Agri-Food Biotechnology Institute, Knowledge City, Sector-81, SAS Nagar, Punjab, India.

Neurochemistry International
|August 20, 2023
PubMed

Insights

Diabetes impairs cognitive function through epigenetic changes, specifically reduced histone acetylation in the brain. This study reveals elevated histone deacetylase (HDAC) activity contributes to memory deficits in diabetic mice.

Area of Science:

  • Neuroscience
  • Epigenetics
  • Metabolic Disorders

Background:

  • Diabetes mellitus (Type 1 and Type 2) is linked to central nervous system (CNS) complications, including cognitive dysfunction.
  • The underlying epigenetic mechanisms, particularly histone acetylation, contributing to diabetes-induced cognitive decline remain poorly understood.

Purpose of the Study:

  • To investigate the role of histone acetylation and deacetylation in cognitive dysfunction in Type 1 and Type 2 diabetic mouse models.
  • To explore the impact of altered epigenetic modifications on memory-related gene expression and the potential of targeting histone deacetylase (HDAC) activity for therapeutic intervention.

Main Methods:

  • Induction of Type 1 and Type 2 diabetes in mice, followed by assessment of diabetic parameters.
  • Evaluation of cognitive performance using behavioral tests: Morris water maze, novel object recognition, and Y Maze.
  • Histone acetylation/deacetylation profiling, HAT/HDAC activity assays, and protein/mRNA expression analysis of specific HDACs in brain regions (cortex, hippocampus).
  • Pharmacological inhibition of HDAC activity using Trichostatin A (TSA) to assess its effect on cognitive function and gene expression.

Main Results:

  • Diabetic mice (T1D and T2D) exhibited significant cognitive deficits compared to control groups.
  • A notable decrease in H3K9/14 and H4K12 acetylation was observed in the cortex and hippocampus of diabetic mice.
  • Elevated histone deacetylase (HDAC) activity, specifically increased expression of HDAC 2 and HDAC 3, correlated with reduced histone acetylation.
  • Reduced acetylation was associated with transcriptional repression of memory-associated genes (BDNF, SYP, PSD-95).
  • Pharmacological inhibition of HDACs with TSA ameliorated cognitive impairments and restored the expression of memory-related genes.

Conclusions:

  • Epigenetic dysregulation, characterized by reduced histone acetylation due to increased HDAC activity, plays a crucial role in diabetes-associated cognitive dysfunction.
  • Targeting HDACs presents a promising therapeutic strategy for mitigating memory deficits in diabetic individuals.
  • This research provides critical insights into the molecular mechanisms underlying diabetes-related memory impairment, paving the way for novel therapeutic development.
Keywords:
BrainCognitionDiabetesEpigeneticsHistone acetylationHistone deacetylases (HDACs)

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