Early epigenetic changes of Alzheimer's disease in the human hippocampus

Epigenetics. 2020 Oct;15(10):1083-1092. doi: 10.1080/15592294.2020.1748917. Epub 2020 Apr 7.

Abstract

The discovery of new biomarkers would be very valuable to improve the detection of early Alzheimer's disease (AD). DNA methylation marks may serve as epigenetic biomarkers of early AD. Here we identified epigenetic marks that are present in the human hippocampus from the earliest stages of AD. A previous methylome dataset of the human AD hippocampus was used to select a set of eight differentially methylated positions (DMPs) since early AD stages. Next, bisulphite pyrosequencing was performed in an expanded homogeneous cohort of 18 pure controls and 35 hippocampal samples with neuropathological changes of pure AD. Correlation between DNA methylation levels in DMPs and phospho-tau protein burden assessed by immunohistochemistry in the hippocampus was also determined. We found four DMPs showing higher levels of DNA methylation at early AD stages compared to controls, involving ELOVL2, GIT1/TP53I13 and the histone gene locus at chromosome 6. DNA methylation levels assessed by bisulphite pyrosequencing correlated with phospho-tau protein burden for ELOVL2 and HIST1H3E/HIST1H3 F genes. In this discovery study, a set of four epigenetic marks of early AD stages have been identified in the human hippocampus. It would be worth studying in-depth the specific pathways related to these epigenetic marks. These early alterations in DNA methylation in the AD hippocampus could be regarded as candidate biomarkers to be explored in future translational studies.

Abbreviations: AD: Alzheimer's disease; DMPs: Differentially methylated positions; CSF: Cerebrospinal fluid; βA42: β-amyloid 42; PET: positron emission tomography; 5mC: 5-methyl cytosine; CpG: cytosine-guanine dinucleotides; ANK1: ankyrin-1; BIN1: amphiphysin II; p-tau: hyperphosphorylated tau; CERAD: Consortium to Establish A Registry for Alzheimer's Disease; SD: standard deviation; ANOVA: one-way analysis of variance; VLCFAs: very long-chain fatty acids; DHA: docosahexaenoic acid; mTOR: mechanistic target of rapamycin.

Keywords: Early Alzheimer ’s disease; DNA methylation; ELOVL2; GIT1; biomarkers; epigenetics; fatty acid; hippocampus; histone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Aspartate Aminotransferase, Cytoplasmic / genetics
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Fatty Acid Elongases / genetics
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Histones / genetics
  • Humans
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • ELOVL2 protein, human
  • Histones
  • MAPT protein, human
  • tau Proteins
  • Fatty Acid Elongases
  • Aspartate Aminotransferase, Cytoplasmic
  • GOT1 protein, human

Grants and funding

This work was supported by the European Regional Development Fund; Instituto de Salud Carlos III [FIS PI13/02730 and PI17/02218]; ‘la Caixa’ Foundation (ES); PRECIPITA platform (Spanish foundation for science and technology-FECYT); Fundación Caja-Navarra; The Basque Foundation for Health Innovation and Research [BIO12/ALZ/007]; Trans-Pyrenean Biomedical Research Network (REFBIOI and REFBIOII); Spanish Government [PFIS fellowship FI18/00150]; Government of Navarra [Doctorados industriales 2018-2020]; ‘la Caixa’ Foundation and Fundación Caja-Navarra [Programa de intensificación].