Gene-Specific DNA methylation linked to postoperative cognitive dysfunction in apolipoprotein E3 and E4 mice

Katie J. Schenning, Sarah Holden, Brett A. Davis, Amelia Mulford, Kimberly A. Nevonen, Joseph F. Quinn, Jacob Raber, Lucia Carbone, Nabil J. Alkayed

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4, compared to APOE3, and epigenetic modifications caused by exposure to anesthesia and surgery. Objective: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. Methods: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. Results: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer's disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. Conclusion: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning.

Original languageEnglish (US)
Pages (from-to)1251-1268
Number of pages18
JournalJournal of Alzheimer's Disease
Volume83
Issue number3
DOIs
StatePublished - 2021

Keywords

  • Alzheimer's disease
  • DNA methylation
  • anesthesia
  • apolipoprotein E4
  • behavior
  • ephrins
  • epigenomics
  • hippocampus
  • postoperative cognitive complications
  • surgery

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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