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

Article type: Research Article

Authors: Schenning, Katie J.^{a; *} | Holden, Sarah^b | Davis, Brett A.^c | Mulford, Amelia^b | Nevonen, Kimberly A.^c | Quinn, Joseph F.^d | Raber, Jacob^{b; d; e} | Carbone, Lucia^{c; f; g; h} | Alkayed, Nabil J.^{a; c}

Affiliations: [a] Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA | [b] Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA | [c] Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA | [d] Department of Neurology, Oregon Health & Science University, Portland, OR, USA | [e] Department of Radiation Medicine, Division of Neuroscience, ONPRC, Portland, OR, USA | [f] Division of Genetics, Oregon National Primate Research Center, Portland, OR, USA | [g] Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA | [h] Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA

Correspondence: [*] Correspondence to: Katie J. Schenning, MD, MPH, MCR, Mail Code L459, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. Tel.: +1 503 494 7641; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, anesthesia, apolipoprotein E4, behavior, DNA methylation, ephrins, epigenomics, hippocampus, postoperative cognitive complications, surgery

DOI: 10.3233/JAD-210499

Journal: Journal of Alzheimer's Disease, vol. 83, no. 3, pp. 1251-1268, 2021