Genotype-dependent reconfiguration of hippocampal transcriptional responses to anesthesia/surgery at 24 h in 5xFAD mice: an exploratory interaction-based analysis
Abstract
Background: Perioperative neurocognitive disorders (PND) are recognized complications after anesthesia and surgery. Alzheimer-related brain states may increase vulnerability, but whether this susceptibility reflects a quantitatively larger or qualitatively distinct acute molecular response remains unclear. We addressed this question using a 5xFAD mouse cohort as an exploratory model of an amyloid-associated brain state.
Methods: Hippocampal bulk RNA sequencing was performed in 4-month-old female wild-type (WT) and 5xFAD mice 24 h after control handling or combined isoflurane anesthesia and abdominal surgery ( n = 3 per factorial cell). DESeq2 was used to estimate genotype, exposure, and genotype-by-exposure effects. Additional sensitivity analyses included effect-size filtering, 12 leave-one-sample-out fits, edgeR quasi-likelihood modeling, and Cook’s-distance diagnostics. Mouse Hallmark gene-set enrichment analysis (GSEA), four marker-based cell-type-associated expression scores, and two public mouse transcriptomic datasets were used for pathway and external context.
Results: WT and 5xFAD within-genotype contrasts identified 20 and 3 exposure-associated genes, respectively, at false discovery rate (FDR) < 0.05. The DESeq2 interaction identified 53 genes at FDR < 0.05; 37 also had |interaction log2FC| ≥ 1. All 53 had opposite-signed exposure-effect estimates in WT and 5xFAD mice, although separate within-genotype significance was not required. All retained their direction in 12 leave-one-out fits and in edgeR, and none exceeded the Cook’s-distance cutoff. However, no gene reached genome-wide FDR < 0.05 in edgeR, indicating method-dependent gene-level significance. Interaction-ranked GSEA identified 10 Hallmark pathways at FDR < 0.05, including positive interaction enrichment of TNF-alpha/NF-kappaB and interferon programs and negative interaction enrichment of oxidative phosphorylation and lipid/metabolic programs. All 10 retained direction and FDR < 0.05 in edgeR-ranked GSEA. None of the four marker-based scores had a significant interaction. No highlighted gene replicated at FDR < 0.05 in the external datasets.
Conclusions: In this small exploratory cohort, the 5xFAD genotype was associated with a directionally reorganized 24-h hippocampal transcriptional response to combined anesthesia and surgery. Pathway-level immune-metabolic interaction patterns were more robust than individual-gene significance. The findings do not establish a perioperative neurocognitive disorder phenotype, distinguish anesthesia from surgical effects, or validate biomarkers; they provide hypotheses for larger, longitudinal, behaviorally phenotyped, and experimentally validated studies.
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BibTeX
@article{wang2026genotypedependent,
title = {{Genotype-dependent reconfiguration of hippocampal transcriptional responses to anesthesia/surgery at 24 h in 5xFAD mice: an exploratory interaction-based analysis}},
author = {Shengjie Wang and Jiwei Song and Shaojun Sun and Renlong Xiao and Zhiyi Zhang and Junyao Zhang and Junyan Yao},
journal = {BMC Genomics},
year = {2026},
month = oct,
doi = {10.1186/s12864-026-13390-7},
url = {https://link.springer.com/10.1186/s12864-026-13390-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genotype-dependent reconfiguration of hippocampal transcriptional responses to anesthesia/surgery at 24 h in 5xFAD mice: an exploratory interaction-based analysis
AU - Shengjie Wang
AU - Jiwei Song
AU - Shaojun Sun
AU - Renlong Xiao
AU - Zhiyi Zhang
AU - Junyao Zhang
AU - Junyan Yao
PY - 2026
DA - 2026/10/08
JO - BMC Genomics
DO - 10.1186/s12864-026-13390-7
UR - https://link.springer.com/10.1186/s12864-026-13390-7
AB - Background: Perioperative neurocognitive disorders (PND) are recognized complications after anesthesia and surgery. Alzheimer-related brain states may increase vulnerability, but whether this susceptibility reflects a quantitatively larger or qualitatively distinct acute molecular response remains unclear. We addressed this question using a 5xFAD mouse cohort as an exploratory model of an amyloid-associated brain state. Methods: Hippocampal bulk RNA sequencing was performed in 4-month-old female wild-type (WT) and 5xFAD mice 24 h after control handling or combined isoflurane anesthesia and abdominal surgery ( n = 3 per factorial cell). DESeq2 was used to estimate genotype, exposure, and genotype-by-exposure effects. Additional sensitivity analyses included effect-size filtering, 12 leave-one-sample-out fits, edgeR quasi-likelihood modeling, and Cook’s-distance diagnostics. Mouse Hallmark gene-set enrichment analysis (GSEA), four marker-based cell-type-associated expression scores, and two public mouse transcriptomic datasets were used for pathway and external context. Results: WT and 5xFAD within-genotype contrasts identified 20 and 3 exposure-associated genes, respectively, at false discovery rate (FDR) < 0.05. The DESeq2 interaction identified 53 genes at FDR < 0.05; 37 also had |interaction log2FC| ≥ 1. All 53 had opposite-signed exposure-effect estimates in WT and 5xFAD mice, although separate within-genotype significance was not required. All retained their direction in 12 leave-one-out fits and in edgeR, and none exceeded the Cook’s-distance cutoff. However, no gene reached genome-wide FDR < 0.05 in edgeR, indicating method-dependent gene-level significance. Interaction-ranked GSEA identified 10 Hallmark pathways at FDR < 0.05, including positive interaction enrichment of TNF-alpha/NF-kappaB and interferon programs and negative interaction enrichment of oxidative phosphorylation and lipid/metabolic programs. All 10 retained direction and FDR < 0.05 in edgeR-ranked GSEA. None of the four marker-based scores had a significant interaction. No highlighted gene replicated at FDR < 0.05 in the external datasets. Conclusions: In this small exploratory cohort, the 5xFAD genotype was associated with a directionally reorganized 24-h hippocampal transcriptional response to combined anesthesia and surgery. Pathway-level immune-metabolic interaction patterns were more robust than individual-gene significance. The findings do not establish a perioperative neurocognitive disorder phenotype, distinguish anesthesia from surgical effects, or validate biomarkers; they provide hypotheses for larger, longitudinal, behaviorally phenotyped, and experimentally validated studies.
SN - 1471-2164
ER -