Epigenetic Changes in Alzheimer’s and Huntington’sS Disease : A semi-quantitative analysis of histone changes

Abstract

Histone acetylation is an epigenetic mechanism that plays a critical role in the regulation of gene transcription, DNA damage repair and DNA replication. Histone acetylation homeostasis is maintained by a balance in the activity of histone deacetylases (HDAC) and acetyltransferases. Disruption in their activity can lead to malfunctioning cells, cell death and disease. There is increasing evidence suggesting that deregulation of histone acetylation and consequential effects leading to aberrant gene expression may influence neurodegenerative disease pathogenesis. To date, rodent models of Huntington’s disease (HD) or Alzheimer’s disease (AD) have generally exhibited evidence for histone hypoacetylation and reduced gene expression in disease pathogenesis. The use of HDAC inhibitors (HDACi) to restore histone acetylation levels and gene expression of downregulated genes has shown promise in these models but so far not in the clinic. Furthermore the state of histone acetylation in human HD and AD brain has not been previously characterised. This discrepancy and lack of correlation in HDACi based therapeutic outcomes between lab and clinic formed the foundation of this current study. Initially semi-quantitative image analysis methods were developed to quantify histone changes. These methods were then used to investigate histone changes in the inferior temporal gyrus and hippocampus of AD and the motor cortex, sensory cortex and cingulate gyrus of HD post mortem brains compared to age and sex matched neurologically normal control brains. Results obtained from semi-quantitative image analysis and Western blot analyses collectively demonstrated that histone H4 is markedly increased (independent of changes in total histone protein) in all regions of interest in HD brains compared to controls. Unlike HD however, histone acetylation increases in AD brains were significantly correlated with changes in total histone protein suggesting different mechanisms of epigenetic deregulation at work in these two diseases. These observations from the human brain highlight not only species differences but raise caution for current epigenome based therapeutic strategies and highlight the need for further investigation and characterisation of the human epigenome, in order to fully understand and develop potential epigenetic therapies to prevent and/or alleviate AD and HD pathogenesis.