Dysregulation of histone acetylation pathways in hippocampus and frontal cortex of Alzheimer's disease patients

Eur Neuropsychopharmacol. 2020 Apr:33:101-116. doi: 10.1016/j.euroneuro.2020.01.015. Epub 2020 Feb 11.

Abstract

Memory impairment is the main feature of Alzheimer's disease (AD). Initial impairments originate in the temporal lobe area and propagate throughout the brain in a sequential manner. Epigenetic mechanisms, especially histone acetylation, regulate plasticity and memory processes. These may be dismantled during the disease. The aim of this work was to establish changes in the acetylation-associated pathway in two key brain regions affected in AD: the hippocampus and the F2 area of frontal cortex in end-stage AD patients and age-matched controls. We found that the F2 area was more affected than the hippocampus. Indeed, CREB-Binding Protein (CBP), P300/CBP-associated protein (PCAF), Histone Deacetylase 1 (HDAC1) and HDAC2 (but not HDAC3) levels were strongly decreased in F2 area of AD compared to controls patients, whereas only HDAC1 was decreased and CBP showed a downward trend in the hippocampus. At the histone level, we detected a substantial increase in total (H3 and H2B) histone levels in the frontal cortex, but these were decreased in nuclear extracts, pointing to a dysregulation in histone trafficking/catabolism in this brain region. Histone H3 acetylation levels were increased in cell nuclei mainly in the frontal cortex. These findings provide evidence for acetylation dysfunctions at the level of associated enzymes and of histones in AD brains, which may underlie transcriptional dysregulations and AD-related cognitive impairments. They further point to stronger dysregulations in the F2 area of the frontal cortex than in the hippocampus at an end-stage of the disease, suggesting a differential vulnerability and/or compensatory mechanisms efficiency towards epigenetic alterations.

Keywords: Alzheimer's disease; F2 area of frontal cortex; Hippocampus; Histone acetyltransferase (CBP, PCAF); Histone deacetylase (HDAC1, HDAC2 and HDAC3); Histones (H2B and H3).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • CREB-Binding Protein / metabolism
  • Epigenesis, Genetic
  • Female
  • Hippocampus / enzymology
  • Hippocampus / metabolism*
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylases / metabolism*
  • Histones / metabolism*
  • Humans
  • Male
  • Metabolic Networks and Pathways
  • Prefrontal Cortex / enzymology
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / pathology

Substances

  • Histones
  • CREB-Binding Protein
  • CREBBP protein, human
  • HDAC1 protein, human
  • HDAC2 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases