Gene-Specific DNA Methylation Linked to Postoperative Cognitive Dysfunction in Apolipoprotein E3 and E4 Mice

Area of Science:

• Neuroscience
• Genetics
• Epigenetics

Background:

• Older adults undergoing surgery face increased risks of postoperative neurocognitive disorders (NCD).
• Mechanisms of NCD are not fully understood but may involve genetic factors like APOE4 and epigenetic changes from anesthesia/surgery.
• APOE isoforms (E3 and E4) are implicated in cognitive function and Alzheimer's disease risk.

Purpose of the Study:

• To investigate if APOE4 mice show greater postoperative cognitive impairment than APOE3 mice.
• To determine if differential DNA methylation in learning/memory brain regions is associated with postoperative cognitive changes.
• To explore the role of APOE genotype in epigenetic responses to surgery and anesthesia.

Main Methods:

• Used 16-month-old mice with humanized APOE3 or APOE4 genes.
• Subjected mice to laparotomy surgery under isoflurane anesthesia or a sham procedure.
• Conducted postoperative behavioral tests and genome-wide DNA methylation analysis.

Main Results:

• Surgery and anesthesia impaired cognition in APOE3 mice but not APOE4 mice, possibly due to APOE4's lower baseline cognition.
• Cognitive deficits in APOE3 mice correlated with hypermethylation of genes in the Ephrin pathway, crucial for synaptic plasticity and learning.
• Genes like Scratch Family Transcriptional Repressor 2 showed altered methylation in both APOE3 and APOE4 mice post-surgery.

Conclusions:

• Postoperative neurocognitive and behavioral outcomes are influenced by baseline cognitive status.
• APOE isoform-dependent epigenetic modifications in genes related to memory and learning are associated with surgery/anesthesia effects.
• Findings highlight the interplay between genetics, epigenetics, and environmental factors in postoperative cognitive health.